Reviews of Physiology, Biochemistry and Pharmacology, Vol. 175

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Reviews of Physiology, Biochemistry and Pharmacology 175

Reviews of Physiology, Biochemistry and Pharmacology

More information about this series at http://www.springer.com/series/112

Bernd Nilius  Pieter de Tombe  Thomas Gudermann  Reinhard Jahn  Roland Lill Editors

Reviews of Physiology, Biochemistry and Pharmacology 175

Editor in Chief Bernd Nilius Department of Cellular and Molecular Medicine KU Leuven Leuven, Belgium Editors Pieter de Tombe Heart Science Centre The Magdi Yacoub Institute Harefield, United Kingdom Reinhard Jahn Department of Neurobiology Max Planck Institute for Biophysical Chemistry Go¨ttingen, Germany

Thomas Gudermann Walther-Straub Institute for Pharmacology and Toxicology Ludwig-Maximilians University of Munich Munich, Germany Roland Lill Department of Cytobiology University of Marburg Marburg, Germany

ISSN 0303-4240 ISSN 1617-5786 (electronic) Reviews of Physiology, Biochemistry and Pharmacology ISBN 978-3-319-95287-1 ISBN 978-3-319-95288-8 (eBook) https://doi.org/10.1007/978-3-319-95288-8 © Springer Nature Switzerland AG 2018 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Contents

Insulin-Like Growth Factor 1 in the Cardiovascular System . . . . . . . . . . Gabriel A. Aguirre, Jose´ Luis Gonza´lez-Guerra, Luis Espinosa, and Inma Castilla-Cortazar

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Potential of Cationic Liposomes as Adjuvants/Delivery Systems for Tuberculosis Subunit Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Farzad Khademi, Ramezan Ali Taheri, Amir Abbas Momtazi-Borojeni, Gholamreza Farnoosh, Thomas P. Johnston, and Amirhossein Sahebkar Targeting Oxidative Stress for the Treatment of Liver Fibrosis . . . . . . . . 71 Theerut Luangmonkong, Su Suriguga, Henricus A. M. Mutsaers, Geny M. M. Groothuis, Peter Olinga, and Miriam Boersema

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Rev Physiol Biochem Pharmacol (2018) 175: 1–46 DOI: 10.1007/112_2017_8 © Springer International Publishing AG 2018 Published online: 3 January 2018

Insulin-Like Growth Factor 1 in the Cardiovascular System Gabriel A. Aguirre, José Luis González-Guerra, Luis Espinosa, and Inma Castilla-Cortazar Contents 1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 IGF1 and IGFBP Physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Insulin-Like Growth Factor 1 Receptor’s Downstream Road in the Heart . . . . . . . . . . . . . . . . . 3.1 Canonical IGF1 Signalling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2 Recent Advances in Non-canonical Cardiomyocytes IGF1 Signalling . . . . . . . . . . . . . . . 4 The Cardiovascular System as a Direct Target for IGF1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 IGF1 and Metabolism: The Onset for Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 IGF1 and Atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 IGF1 and the Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 IGF1 Deficiency and Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.5 IGF1 Treatment: Future and Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract Non-communicable diseases, such as cardiovascular diseases, are the leading cause of mortality worldwide. For this reason, a tremendous effort is being made worldwide to effectively circumvent these afflictions, where insulin-like growth factor 1 (IGF1) is being proposed both as a marker and as a central cornerstone in these diseases, making it an interesting molecule to focus on. Firstly, at the initiation of metabolic deregulation by overfeeding, IGF1 is decreased/inhibited. Secondly, such deficiency seems to be intimately related to the onset of MetS and establishment of vascular derangements leading to atherosclerosis and finally playing a definitive part in cerebrovascular and myocardial accidents, where IGF1 deficiency seems to render these organs vulnerable to oxidative and apoptotic/necrotic damage. Several human cohort correlations together with G. A. Aguirre, J. L. González-Guerra, and L. Espinosa Escuela de Medicina, Tecnologico de Monterrey, Monterrey, Nuevo León, Mexico I. Castilla-Cortazar (*) Escuela de Medicina, Tecnologico de Monterrey, Monterrey, Nuevo León, Mexico Fundación de Investigación HM Hospitales, Madrid, Spain e-mail: [email protected]; [email protected]

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basic/translational experimental data seem to confirm deep IGF1 implication, albeit with controversy, which might, in part, be given by experimental design leading to blurred result interpretation. Keywords Atherosclerosis · Cardiovascular disease · Cardiovascular system · IGF1 · Metabolic syndrome

1 Introduction Non-communicable diseases such as diabetes, cardiovascular diseases, or cancer are the leading cause of mortality worldwide (Lee 2014). On the other hand, the term cardiovascular diseases (CVD), as defined by the World Health Organization, includes myocardial infarction and cerebrovascular disease. According to the World Economic Forum’s 2009 report, these diseases have been postulated as endangering the world’s economy, even being perceived as more threatening than economic crises, natural disasters, or pandemic influenza (Narayan et al. 2010). For this reason, a tremendous effort is being made worldwide to effectively circumvent these afflictions, where insulin-like growth factor 1 (IGF1) is being proposed both as a marker and as a central cornerstone in these diseases, making it an interesting molecule to focus on for reasons that will be thoroughly described along the following lines. In the last decade, a prodigious amount of information concerning IGF1 arose regarding its newly discovered actions on every tissue. However, with no doubt, the area with the greatest amount of new data has been mitochondrial protection, metabolism, the cardiovascular system (CVS), and cytoprotection with antioxidant properties in several organs. Herein we will present and integrate the most relevant findings regarding IGF1 actions in the cardiovascular system. Before getting into the matter, IGF1, its biochemistry, and physiology will be presented, with canonical and non-canonical pathways and receptor interactions. At first, it will be briefly presented the role that IGF1 plays in metabolism. This is an important fact to mention in order to understand its implication from before the onset of any cardiovascular complication and to introduce the idea that IGF1 might be implicated from the very early stages of metabolic deregulation all the way to cardiovascular recovery after an accident has occurred. However, no deep immersion will be made as this topic has been recently and thoroughly revised (Aguirre et al. 2016). In brief, IGF1 acts as a cornerstone in the growth hormone (GH)/IGF1/insulin axis, which can be deregulated by overfeeding and sedentary lifestyle. Such alteration ends up by downregulating or inhibiting IGF1 and eliciting insulin resistance, with its concomitant consequences that will be further discussed. Thereafter, atherosclerosis will be reviewed integrating endothelial/vascular effects with immunologic ones, in the form of a progressive disease, and inserting, wherever it has been discovered, IGF1 actions in the vasculature and the immune system. Succinctly, IGF1 both acts as an anti-inflammatory agent and by regulating

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the immune response. Then, IGF1 actions in the vasculature (regulating certain factors like eNOS and oxidative damage via Nrf2) and in the heart’s development and homeostasis will coronate its implication in these pathologies. After metabolic deregulation has led to metabolic syndrome (MetS) and atherosclerosis, clinical data of IGF1 in CVD will be reconciled, in which the majority sustain that IGF1 levels correlate with either prognosis, severity, or outcome, however, with a certain degree of controversy. Lastly, IGF1 as a treatment option will be debated, remarking its beneficial actions and unwanted effects from different trials for different diseases. This review offers a new insight that brings together, firstly, a novel perspective of non-canonical IGF1 pathways. Thence after bringing simultaneously metabolic syndrome and atherosclerosis, describing vascular and immunologic effects. IGF1 implication in the system as a whole will be established. It also resumes novel findings of direct IGF1 actions in the heart (basic and translational) together with clinical data from CVD and stroke. Altogether it gives a novel and undivided approach to the totality of the pathophysiological CVD entity.

2 IGF1 and IGFBP Physiology IGF1 conforms a large protein of 70 amino acids with several structural and functional domains. This pleiotropic hormone possesses endocrine, paracrine, and autocrine effects. It also shares structural homology with IGF2 and proinsulin (over 60% homology) (Rinderknecht and Humbel 1978; Flier et al. 1997). IGF1 is synthesised in virtually every tissue (D’Ercole et al. 1984), yet mainly produced by the liver (responsible for 75% of the circulating hormone) following GH stimulation. Conversely, IGF1 acts as a negative regulator for GH secretion in the hypothalamus via somatostatin production in the adrenal gland (Berelowitz et al. 1981; Böni-Schnetzler et al. 1991; Ohlsson et al. 2009). This inhibitory negative feedback mechanism is very important for metabolic coordination (Fig. 1). IGF1 is strongly regulated by the professed insulin-like growth factor-binding proteins (IGFBPs), which increase IGF1 half-life, from minutes to hours, most commonly by forming a heterotrimeric complex with acid-labile subunit and IGFBP3. However, binding to this complex hinders its attachment to the type 1 insulin-like growth factor 1 receptor (IGF1R) (Clemmons 1998; Rosenfeld et al. 2000; Rajpathak et al. 2009; Martín-Estal et al. 2015). For this reason, the ratio between IGF1 and IGFBP3 is considered the clinically relevant value to roughly estimate biologically active/ available IGF1. Nevertheless, being vaguely precise as its regulation system goes beyond such simplicity. IGFBPs also operate by guiding IGF1 to tissues to inhibit or potentiate IGF1 actions. IGFBPs may as well act as independent substrates (without bound IGF1) for IGF1R and/or specific IGFBP membrane, intracellular, or nuclear receptors (Clemmons 1998; Rosenfeld et al. 2000; Rajpathak et al. 2009). Up until now, six high-affinity IGFBPs have been described (Clemmons 1998; Rosenfeld et al. 2000; Rajpathak et al. 2009). Likewise, insulin-like growth factor-binding

Fig. 1 Model of GH/IGF1 axis regulation and IGF1 target organs. Negative feedback mechanism induced by IGF1 regulates the GH/IGF1 axis: IGF1 inhibits GH gene expression by stimulating somatostatin secretion. GH secretion stimulates IGF1 secretion in the liver. GHRH (growth hormone-releasing hormone) stimulates GH secretion, which stimulates IGF1 secretion

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protein-related proteins (IGFBPrPs) have been proposed, which assist IGF1, but still, exactly how is not yet completely understood (Liu et al. 2002; López-Bermejo et al. 2003). Nonetheless, it is worth mentioning that IGF1 has a complex post-transcriptional and post-translational modification process. Six exons make up the IGF1 gene, which undergoes alternative splicing, dependent upon transcription starting sites, and post-translational modification, leading to several isoforms in different organs (Temmerman et al. 2010). For what is known today, two classes of posttranscriptional modification can occur. One that alters the 50 end of the transcript and another altering 30 ends. For the former, affecting the N-terminal signal peptide, if the transcription initiates at exon 1, it then skips exon 2 which results in removal of a 186-base long sequence. These transcripts are termed as Class 1 transcripts. On the other hand, transcripts that have exon 2 and usually lack exon 1 are known as Class 2 transcripts (Shavlakadze et al. 2005). Conversely, 30 alternative splicing affecting the C-terminal peptide extension adds further complexity. For example, when a Class 1 transcript undergoes partial splicing of exon 4 and skips exons 5–6, 19 amino acids are added to the common 16 amino acids encoded by exon 4, thus generating a 35-amino acid long E-peptide in humans, termed Class 1 Ea-peptide. This peptide is the common IGF1 isoform mainly expressed by the liver (circulating isoform) and skeletal muscle; however, virtually every tissue makes this isoform (Shavlakadze et al. 2005; Stavropoulou and Halapas 2009; Temmerman et al. 2010). Moreover, human Eb-peptide contains additional 61 amino acids encoded by exon 5 and a nucleus-nucleolus import sequence, and Ec (also called mechano growth factor, MGF, Eb in mice) expresses full exon 4, 49 bp of exon 5, and then exon 6 (exons 4–6) yielding an extension peptide with a total predicted length of 41 amino acids. Eb and Ec (MGF) peptides both were found to be expressed in the liver; however Ec (MGF) is highly expressed in injured muscles (Shavlakadze et al. 2005). Of recent discovery, the mIGF1 isoform, comprising a Class 1 signal peptide and a C-terminal Ea extension peptide, is highly expressed in neonatal tissues and in the adult liver but decreases during ageing in extrahepatic tissues. However its expression is reactivated in response to damage and has been attributed dramatic cell survival and renewal actions in senescent muscle (Santini et al. 2006). Then, posttranslational modifications (protease cleavage) give rise to additional isoforms of the unprocessed (precursor) IGF1, which differ by the length of the amino-terminal signal peptide and structure of the so-called extension peptide (E-peptide) on the carboxy-terminal end, which are both cleaved to yield a 70-amino-acid-long singlechain mature IGF1 polypeptide with three intrachain disulphide bridges. IGF1 contains a B amino-terminal domain, an A domain, and a C domain. However, unlike proinsulin, IGF1 polypeptides also contain a D-carboxy-terminal domain (Shavlakadze et al. 2005). IGF2 physiological role is still unclear. But, still, important functions have been characterised for foetus development and cerebral protection (Castilla-Cortázar et al. 2011; Garcia-Fernandez et al. 2011). IGF2 can act over its own receptor (IGF2 receptor – IGF2R), which is a manose-6-phosphate transmembrane protein with undetermined actions, or it can bind to and activate IGF1R, despite with less affinity

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than IGF1 but greater than insulin (insulin < IGF2 < IGF1). It is thought that IGF2R job may be to function as a scavenger receptor, sequestering IGF2 and IGF1 from the extracellular medium and targeting them for destruction. Additionally, IGF2 can also interact with the insulin (IR) and hybrid receptors, albeit with reduced affinity (Wolf et al. 1998) (Fig. 2). As depicted in Fig. 1, IGF1 has been associated with many physiological actions, namely, tissue growth and development, proliferation, pro-survival/anti-ageing, anabolic (classic ones), lipid metabolism, anti-inflammatory, antioxidant, neuroprotective, and hepato-protective properties (Castilla-Cortazar et al. 1997a, 2000; Pascual et al. 2000; Muguerza et al. 2001a; Mirpuri et al. 2002; García-Fernández et al. 2003, 2005a, 2008; Castilla-Cortázar et al. 2004; Conchillo et al. 2005; Pérez et al. 2008; Puche et al. 2008a). One of the most interesting roles is the mitochondrial protection: preserving these organelles from oxidative damage generated by augmented metabolism, reducing intra-mitochondrial production of free radicals, and increasing ATP synthesis and O2 usage efficiency (García-Fernández et al. 2008; Pérez et al. 2008; Puche et al. 2008a).

Fig. 2 Schematic structure of insulin, IGFs, and their receptors. Resemblances between insulin and IGFs allow them to cross-interact with each other’s receptors. Green arrows represent binding only at supraphysiological concentrations. Red arrows represent binding at physiological concentrations. Black arrows depict the preferred receptor attending to affinity. *IGF2 can also interact with IGF1R, hybrid receptors, and the insulin receptor, with a lower affinity. IGF1 can also bind to IGF2R, albeit with less affinity to that of its putative receptor

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3 Insulin-Like Growth Factor 1 Receptor’s Downstream Road in the Heart 3.1

Canonical IGF1 Signalling

IGF1 can trigger its putative receptor (type 1 IGF1R) or it can also bind to the IR, although with less affinity (LeRoith et al. 1995; Kim and Accili 2002; Chitnis et al. 2008a). IGF1R comprises a α2β2 heterotetrameric complex of approximately 400 kDa. The two α2 subunits make up the extracellular ligand-binding domain; these extend to the membrane-spanning β2 subunits which possess its tyrosine kinase activity at the C-terminal intracellular domain. In addition, a hybrid receptor (type 2 IGF1R) with components of the IR (one α and one β-chain) and the IGF1R (one α and one β-chain) exists. This receptor can accommodate both insulin and IGF1, but with less affinity to that of their putative receptors (Fig. 2). Insulin binds to IGF1R and hybrid receptors, however only under supraphysiological concentrations (LeRoith et al. 1995; Kim and Accili 2002; Chitnis et al. 2008a). All of these receptors hold tyrosine kinase activity and thereby are potent protein kinase B (PKB/Akt) and mitogen-activated protein kinase (MAPK) pathway initiators (LeRoith et al. 1995; Kim and Accili 2002; Chitnis et al. 2008a). Upon ligand binding, alike ordinary receptor tyrosine kinases, tyrosine transphosphorylation occurs within the cytoplasmic C-terminal domain of the β-chain leading to the attraction of adaptor and coupling molecules that will be further phosphorylated to attract substrates which will be in turn phosphorylated and activated (Adams et al. 2000; De Meyts and Whittaker 2002b). As illustrated in Fig. 3, activated IGF1R possesses a phosphorylated NPXY motif in its intracellular domain which, in cardiomyocytes, serves as a docking site for insulin receptor substrate 1 (IRS1) and Src homology 2 domain-containing (SHC). On the other hand, the IR mostly recruits IRS2 (primarily acting through Akt2, by contrast mostly implicated in metabolism) (Foncea et al. 1997). Through the hybrid receptor, IGF1 can be also linked to metabolic regulation, as this receptor would activate both Akt1 (IGF1R β-chain domain) and Akt2 (IR β-chain domain). IRS1, one of the molecules to be attracted to an activated IGF1R, primarily recruits phosphoinositol triphosphate-kinase (PI3K), which is in turn phosphorylated and activated by IGF1R. PI3K then phosphorylates phosphoinositol diphosphate (PIP2) to PIP3 (triphosphate), which now displays a PH domain. Such PH domain attracts phosphoinositide-dependent kinase 1 (PDK1) and mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which in turn also attract, phosphorylate, and activate Akt1 (De Meyts and Whittaker 2002b). Of interest, Akt1 is one of the most potent and natural inhibitors of apoptosis through the modulation of Bad, Bax, Bcl-2, HSPs, and Caspase 3 proteins. On the other hand, mTOR is implicated in the negative regulation of autophagy (via ULK1/2), activation of protein synthesis, deactivation of protein degradation/turnover (through FoxO transcription factor), and regulation of cell growth (Foncea et al. 1997; De Meyts and Whittaker 2002a; García-Fernández et al. 2005b; Kurmasheva and Houghton 2006; Chitnis et al.

Fig. 3 IGF1 receptor intracellular signalling pathway. IGF1R recruits IRS1 (preferentially to IRS2), SHC, and recently characterised Gαi proteins. IRS1 attracts and activates PI3K, thus stimulating Akt and PKC pathways leading to cell growth (hypertrophy) and survival (apoptosis inhibition). By contrast, SHC binds to SOS and Grb2, activating RAS and hence the MAPK pathway, which promotes cell cycle progression, differentiation, and gene transcription. Lastly, Gαi proteins activate PLC, resulting in IP3 and Ca2+ concentration increase, and inhibit adenylate cyclase causing downregulation of PKA. IGF2R has also been proposed to activate Gαi proteins

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2008b; Bitto et al. 2010; McMahon et al. 2010; Troncoso et al. 2012, 2013; Riehle et al. 2013; Rosenbloom 2015). Conversely, SHC, another important molecule attracted to an activated IGF1R, recruits growth factor receptor-bound protein 2 (Grb2), which consecutively brings son of sevenless (SOS) near Ras (a monomeric G protein), acting as a guanine nucleotide exchange factor (GEF) for Ras, activating it, and then activating Raf (human MAPKKK) and ultimately extracellular signal-regulated kinase (Erk). Erk acts as a strong pro-survival effector molecule, modulating protein activity and gene transcription (Kurmasheva and Houghton 2006).

3.2

Recent Advances in Non-canonical Cardiomyocytes IGF1 Signalling

Recent studies reveal non-canonical pathways for IGF1R in the heart which suggest that Gαi proteins also become activated (Fig. 3), ultimately leading to phospholipase C (PLC) and adenylate cyclase inhibition (Luttrell et al. 1995; Hallak et al. 2000; Kuemmerle and Murthy 2001; Dalle et al. 2001). The former acts by increasing inositol 1,4,5-triphosphate (IP3) and the latter by decreasing cyclic adenosine monophosphate (cAMP), both leading to nuclear Ca2+ oscillations, thereby functioning to regulate metabolic adaptability and genetic transcription. Also, regarding cell growth and protein synthesis, new evidence suggests there is an Akt-independent mTOR/p70S6K pathway for this effect in cardiomyocytes (Song et al. 2005). Additional complexity comes with the discovery of a particular structural organisation for IGF1R signalling microdomains in cardiomyocytes. It has been assumed that the receptor locates in the myofibril plasma membrane; however studies have found that it is also present, albeit in lower concentrations, in the nuclear envelope and sarcolemmal fractions (Tadevosyan et al. 2012). This may explain the rapid actions observed for IGF1 on the cardiomyocyte, as it can act through direct interaction with the nucleus via Ca2+ and cAMP concentrations (Nikolaev et al. 2010; Ibarra et al. 2013). In addition, IGF1R has been found localised at higher concentrations in the deep perinuclear T tubules (Fig. 4), which are in direct apposition to the nucleus (Nikolaev et al. 2010). Note that voltage-activated calcium channels (dihydropyridine receptor – DHPR) locate in the medial portion of the T tubules, not in the deep fragment, co-locating with the sarcolemma in order to activate the ryanodine receptor (RyR). In this context, recall that IGF1R has been found to activate Gαi proteins, therefore stimulating PLC, producing IP3, and opening calcium channels through the IP3 receptor (IP3R). Then, under this scenario, nuclear and sarcolemmal IP3R can be rapidly and selectively activated, triggering changes in the nucleus, being this action compartmentalised and independent to the cytosol’s biochemistry. In this way, such outcomes contribute to Ca2+ tone homeostasis in this tissue. Thus, in cardiomyocytes, IGF1R signalling has a fast and direct inter-organelle communication (Arantes et al. 2012; Bers 2013; Ibarra et al. 2013).

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Fig. 4 Cardiomyocyte IGF1 receptor localisation and signalling. (1) IGF1R and IGF2R, as opposed to dihydropyridine receptor (DHPR, involved in calcium-induced calcium release mechanism for muscle contraction via ryanodine receptor – RyR) which is localised at the medial T tubule fraction (in close contact with the sarcolemma), seem to localise in the deep T tubule fraction in direct apposition to the nuclear envelope and endoplasmic reticulum. (2) Interestingly, IGF1R is also found in the nuclear envelope and endoplasmic reticulum. (3) This could suggest a role for IGF2R in the internalisation of IGF1/IGF2, where instead targeting IGF1/2 for proteolysis, they could activate these intracellular receptors. (4) Also, because both receptors appear to recruit and activate Gαi proteins, they may evoke rapid and independent nuclear calcium changes, both intervening in calcium tone (contraction force and duration) and rapid protein and genetic changes

A plausible role for IGF2R might be, instead of acting as a scavenger internalising and targeting IGF1/2 for proteolysis, to target intracellular IGF1Rs, having a more direct, rapid, and specific interaction. As of recent discovery, IGF2R has shown to activate Gαi proteins within cardiomyocytes (Wang et al. 2015a), possibly aiding in Ca2+ dynamics.

4 The Cardiovascular System as a Direct Target for IGF1 4.1

IGF1 and Metabolism: The Onset for Metabolic Syndrome

For many decades, the “clustering” of metabolic derangements and CVD risk factors has been widely discussed. Nonetheless, the term “metabolic syndrome” has become commonly used since its inception by the “Executive Summary of the Third Report of the National Cholesterol Education Program” (NCEP) in 2001 (Expert Panel on Detection, Evaluation 2001). Thence after, many different concepts and definitions

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were proposed until 2009, when a harmonised definition was finally described (Alberti et al. 2009). According to this definition, a diagnosis of MetS is coined when three of the following five risk factors are present: enlarged waist circumference with population- and country-specific criteria, elevated triglycerides (defined as 150 mg/dL), decreased high-density lipoprotein (HDL) (ranges below 40 mg/dL in men and 50 mg/ dL in women), elevated blood pressure (defined as systolic blood pressure above 130 mmHg or diastolic blood pressure above 85 mmHg), and elevated fasting glucose (defined as blood glucose above 100 mg/dL). This definition includes those patients that are taking medication to manage hypertriglyceridemia, low HDL, hypertension, and hyperglycaemia (Alberti et al. 2009). In general, MetS continues to be a clustering of symptoms that seem to play a major role as CVD and T2D risk factors, raising the necessity of encouraging these patients to pursue lifestyle changes. Moreover, the harmonised definition criteria were found to be a better predictor of CVD than each of its separate components or the Framingham score – this was not applicable for T2D [3]. IGF1 has been shown to possess a direct influence over those factors, and along the following line, we will postulate its implication in the onset (from foetus to adult metabolic dysregulation by western lifestyle) of MetS. However, it has been recently revised (Aguirre et al. 2016) and thus will not enter into much detail other than its implication to CVD. Foetal growth restriction (FGR) has been proven to be a risk factor for adult CVD. Moreover, FGR has been linked to IGF1 deficiency; however, it is still not clear if such deficiency comes from the mother, the placenta, or the foetus (Martín-Estal et al. 2015). All of these facts have been recently proven in a mice model of FGR that developed CVD in the adulthood. In these mice, when administered IGF1 in utero in various forms, adult CVD was abolished (Alsaied et al. 2017). What is more, such effects have been confirmed by others who also proved to be mediated by a deficiency in the mTORC1 pathway (IGF1 pathway) (Hennig et al. 2017) and adult CVD through PI3K (uphill mTORC1) (McMullen 2008). Also, certain polymorphisms in the IGF1 gene have been linked to risk for myocardial infarction, reaffirming a strong relationship between IGF1 and CVD (Aoi et al. 2010). Even when no apparent relation should exist, like in congenital heart disease, a prospective study found that lowered IGF1 and elevated GH correlated with cyanosis, malnutrition, and left ventricular function (Dinleyici et al. 2007). These facts all sustain that IGF1 has a key role in the normal intrauterine development of the CVS as well as during the childhood and that its deficiency could harvest serious and detrimental metabolic and cardiovascular complications in the adulthood. Over the last decade, an overwhelming wave of information concerning IGF1 implications in metabolism has crowded the databases. Much of the metabolic actions mediated by IGF1 in metabolism are secondary to GH suppression, and others are direct actions. The most well-characterised independent IGF1 actions are gluconeogenesis suppression in the kidneys and liver, insulin signal restoration, and uptake of free fatty acids by myocytes (Mauras and Haymond 2005; Clemmons 2006, 2012; Livingstone and Borai 2014; Ren and Anversa 2015). Interestingly, O’Neill and colleagues (2015), very elegantly, demonstrated that the loss of insulin/ IGF1 receptor signalling impairs muscle growth, but not whole-body glucose

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tolerance due to increased membrane localization of glucose transporters (GLUT1 and GLUT4). Nonetheless, the presence of a dominant-negative receptor (a non-functional receptor), even in the absence of functional IR/IGF1R, induces glucose intolerance. This evidence opens a new perspective probably indicating that these receptors possess a different signalling pathway behaviour when the ligand is not present or that they interact with a different set of proteins that provide feedback loops in these cells. However, as the authors comment, the absence of the receptors does not represent physiological events, but gives us a cue for new mechanisms. Moreover, given that muscle utilises even more glucose in the fasted state, this means that myocytes are not performing metabolic flexibility, i.e. using FFA as a fuel during the fasting state, consequently reducing lipid trafficking in the bloodstream, actual route by which IGF1 helps against the pathogenesis of MetS. Increased lipid trafficking through the bloodstream, continuous exposition to elevated levels of insulin, and adipokines secreted in response to excess diet all contribute to the desensitisation of insulin’s signal, setting the start line for MetS. Downregulation of insulin sensitivity causes insulin-dependent adipocytes and myocytes to cease glucose uptake, hence being metabolised to fat in the liver and building up in the bloodstream. Lack of insulin signalling (due to central insulin insensitivity) makes adipocytes release FFAs, while the liver in a futile cycle reprocesses them and releases them into the blood again, also accumulating in the serum. On the other hand, insulin is one of the most powerful inhibitors for IGFBP1 transcription in the liver (Lewitt et al. 2010). Thus, under an insulin resistance scenario, an excess of IGFBP1 sequesters IGF1, making it biologically unavailable. Deprivation of IGF1 also diminishes its insulin-aiming actions and GH secretion inhibition. This contributes to the positive feedback of this whole catastrophe, as the growth hormone receptor (GHR) could also become desensitised and stop signalling the liver to produce IGF1 (Talamantes and Ortiz 2002). In conjugation, GH promotes lipolysis in adipocytes through the β-3 adrenergic receptor, further adding to lipid trafficking (Heffernan et al. 2001; LeRoith and Yakar 2007). These phenomena coupled with IGFBP1 hyper-expression and IGF1/insulin signalling being hijacked by pro-inflammatory factors/signals and together with increased intracellular lipid trafficking all leave IGF1 out of the game for aiding insulin in metabolic orchestration. In this frame, mention of serine phosphorylation of IRSs as a mechanism for insulin resistance is vital (Fig. 5). Increased IR activation, reactive oxygen species (ROS), free fatty acid trafficking, and pro-inflammatory signals all trigger threonine/ serine kinases, which will phosphorylate serine and threonine residues in IRSs, rendering them less prone to tyrosine phosphorylation, i.e. to become activated by IR/IGF1R (LeRoith et al. 1995; Adams et al. 2000). It is believed that IGF1 is capable of rescuing insulin signalling via this mechanism. IGF1R, through its own isoform of IRS (IRS1), which is less sensible to serine phosphorylation and more inclined to tyrosine phosphorylation of other IRS, restores insulin signalling (Zick 2004; Melnik et al. 2011). Inasmuch IGF1 contributes by this mechanism, also its powerful anti-inflammatory effects (Fan et al. 1995; Samstein et al. 1996; Lang et al. 1999) could, in theory, reduce pro-inflammatory signals coming from adipocytes that could also hijack insulin and IGF1 signalling at a serine phosphorylation level.

Fig. 5 Molecular mechanism for insulin resistance. (1) Free fatty acids (FFAs), cellular stress in the form of reactive oxygen species (ROS), pro-inflammatory mediators (such as TNF-α), and the proper negative feedback mechanism of the activated Akt/MAPK pathway all seem to activate IRSs serine/threonine

Insulin-Like Growth Factor 1 in the Cardiovascular System 13

Fig. 5 (continued) kinases. (2) When IRSs get phosphorylated in such serine/threonine residues by these kinases, they become less prone to tyrosine phosphorylation, hence getting inhibited. (3) IRS2 (greater affinity for the insulin receptor – IR) has been found to be much more sensible to Ser/Thr phosphorylation, as opposed to IRS1 (preferentially recruited by IGF1R), which seems to be resistant to such effect and, in fact, appears to possess tyrosine kinase activity with affinity for IRS2. These could potentially mean that IR is prone to become desensitised by FFAs, ROS, and inflammation, while IGF1R is resistant to it, in fact being able to reinstitute IR signalling. (4) Also, IRS1 and IRS2 appear to activate/inhibit distinct mTOR complexes (through recruiting different Akt isoforms). While mTORC2 (insulin receptor signalling) seems to activate threonine/serine kinases as a feedback loop to terminate the receptor’s signal, mTORC1 (IGF1R signalling) appears to oppose to this effect, in theory rescuing insulin’s signal. This mechanism seems more plausible, as the one classically professed which stated that IGF1 activates IR/hybrid receptors. This theory looks less possible, as IGF1 binding to IR only occurs at supraphysiological levels and, what is more, IGF1 is normally downregulated in these scenarios

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4.2

15

IGF1 and Atherosclerosis

The above-described bodily war strategy creates a central alteration that opens the way to the pathogenesis of atherosclerosis, where increased lipid trafficking and subsequent accumulation lead to resident M2 macrophage and adipose tissue activation commencing a chronic low-grade inflammatory state that crosses the physiological threshold. This set of circumstances promotes an oxidative environment that eventually leads to increased LDL accumulation and concomitant oxidation (over physiological levels), setting the onset for atherosclerotic lesions (Navab et al. 1996; Ross 1999; Glass and Witztum 2001). A recent work found under-expressed LDL-related proteins in a partial IGF1-deficient murine model (De Ita et al. 2015), which are necessary for receptor-mediated LDL reuptake by the liver, thereby suggesting an important role in plasma LDL accumulation leading to its subsequent oxidation. If MetS is considered a novel condition of IGF1 deficiency, which is increasingly being suggested (Troncoso et al. 2014a; Ren and Anversa 2015; Aguirre et al. 2016), a metabolic susceptibility leading to atherosclerosis could be directly linked to IGF1. In further sections, relationships found will be carefully revised. Genetic traits play a very important role in atherosclerosis, and some founder genes have been isolated. However, even with the same founder gene and similar cholesterol levels, the heterogeneity of the clinical progression evidences an important role for environmental factors (Glass and Witztum 2001). Nevertheless, whichever is the onset’s leading cause, what remains invariable is IGF1/GH/insulin axis deregulation (as seen in animal models and clinical correlations, detailed in Sect. 4.3), causing free fatty acids (FFAs) and cholesterol to impact metabolic regulation, provoking inflammatory damage leading to atheroma plaques and ultimately cardiovascular accidents. Available evidence suggests that oxidation of the Apo-B protein and lipids from the LDL particle (oxLDL) give rise to the onset of the pathology (Witztum 1994; Navab et al. 1996) by forming the initial fatty streaks. Such modifications can be minimal, where the LDL particle can still be recognised by its receptor (LDLR), or extensive, where only the so-called scavenger receptor can now recognise the particle. Scavenger receptors are mainly expressed by macrophages and smooth muscle cells. There is evidence of physiological oxidation of LDL particles, believed to occur by enzymatic and non-enzymatic means in the extracellular matrix of the artery wall (Schwenke and Carew 1989; Williams and Tabas 1998; Steinberg and Witztum 1999). Myeloperoxidase (MPO), nitric oxide synthase (NOS), and 15-lipoxygenase (15-LO) have been found to directly or indirectly oxidise LDL lipids (Heinecke 1998; Harats et al. 2000). With regard to NOS, it has been found a protective role for endothelial NOS (eNOS), routinely expressed by the endothelium, and a damaging effect by the inducible NOS (iNOS), whose expression prevails upon activation of macrophages. IGF1 is known to reduce MPO and iNOS activity in experimental murine cirrhosis (García-Fernández et al. 2005b) by NF-κβ-independent pathways (Hijikawa et al. 2008). Likewise, IGF1 is a well-known potent vasodilator as

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it upregulates eNOS in endothelial cells of the vasculature (Scharin Täng et al. 2012; Troncoso et al. 2014b). In this way, IGF1 could be of help by regulating MPO, iNOS, and eNOS balance. By contrast, macrophage and T cell recruitment to the arterial wall seems to be triggered by chemoattractants (for instance, MCP-1, secreted by endothelial cells after contact with an oxLDL and TNF-α) and adhesion molecules, and also oxLDL can directly trigger monocyte activation and differentiation to macrophage (Han et al. 1999). Hypercholesterolaemia has been proven to upregulate CCR2 (MCP-1 receptor), thus making monocytes more susceptible by lowering activation sensitivity threshold (Gu et al. 1998; Boring et al. 1998; Gosling et al. 1999). In this sense, metabolic deregulation associated with IGF1 deficiency can be of importance in the very onset of the condition. What is more, TNF-α-activated infiltrating cells are known to produce and secrete IGF1, presumably for immunomodulation (Rom et al. 1988; Kirstein et al. 1992; Fournier et al. 1995). Of importance, IGF1 possesses further anti-inflammatory effects through mitochondrial protection and reactive oxygen species neutralisation (Pérez et al. 2008; Puche et al. 2008a; Sádaba et al. 2016) and by blocking elevation of IL-1β, TNF-α, and neutrophil chemoattractant 1 (Smith 2010). Plus, TNF-α is known to disrupt IGF1 signalling (Anwar 2002), which could negatively contribute to the lesion’s stability and overall smooth muscle homeostasis. Because of this, under an IGF1 deficiency state, the balance (within inflammatory sites) between TNF-α and IGF1 may be disrupted, thus inclining towards exacerbated inflammation. Moreover, IL-10, long known to be an antiinflammatory cytokine, has been found to possess deactivating effects in Th1 cells, macrophages and several other cellular processes acknowledged to interfere with the lesion stability (Glass and Witztum 2001). In parallel, IGF1 is known to upregulate IL-10 mRNA expression in human leucocytes (Kooijman and Coppens 2004), possibly indicating another anti-inflammatory action. Further recruitment and activation take place, leading to the formation of foam cells and antigen presenting to T cells with oxLDL epitopes by macrophages, which will now produce autoantibodies (Glass and Witztum 2001). Autoantibodies have shown to possess a crucial role in the pathophysiology of the disease. Once these antibodies opsonise oxLDL, they cannot be taken up by macrophages, but still continue to stimulate pro-inflammatory signals. It has been found that Th1-derived interferon-γ (IFN-γ) reduces scavenger receptor expression on macrophages, decreases collagen synthesis, and inhibits smooth muscle cell proliferation, although it can also promote cytokine release and antigen-presenting activity (Gupta et al. 1997). In this regard, IGF1 has a powerful implication as it has been proven to downregulate IFN-γ R2 chain display in human T cells, making them insensible to IFN-γ STAT1 signalling (Gupta et al. 1997). For this reason, IGF1 deficiency could lead to an augmented antigen presenting co-activation and cessation of oxLDLs scavenger uptake, along with their consequent accumulation, hence further promoting inflammation. Available evidence show that activation of the CD40 receptor (involved in antigen presentation co-activation) in macrophages, smooth muscle, and endothelial cells promotes atherogenic expression of cytokines, matrix metalloproteinases (MMPs), adhesion molecules, and tissue factor (inducer of the

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coagulation cascade) (Mach et al. 1998). As well, MMPs-secreting macrophages have been linked to an increased susceptibility of plaque rupture, as they contribute to lesion instability by degrading extracellular matrix. This set-up establishes the onset for fibrogenesis in the lesion, making it even more unstable. Recently, an implication of IGF1 in the structure of the extracellular matrix has been found and shown to modulate expression of collagens, connective tissue growth factor, MMPs, and tissue inhibitor of MMPs – TIMPs. It also coordinates adhesion molecules and fibrogenesis in the liver (Castilla-Cortazar et al. 1997b; Muguerza et al. 2001b; Puche and Castilla-Cortázar 2012a, b; Lara-Diaz et al. 2017), possibly suggesting a similar responsibility in other tissues, which might contribute to altered extracellular matrix formation in regeneration processes leading to fibrosis in the plaques. Plaque ruptures are more likely to occur in lesions with fibrous caps, high concentrations of lipid-filled macrophages, and those with large necrotic cores. Apoptosis and necrosis play a very important role in this condition by forming the necrotic core as the release of oxidised and insoluble lipids from necrotic cells undoubtedly contributes to further lesion exacerbation and destabilisation. Additionally, apoptosis of smooth muscle and macrophages makes lesion regression likely unfavourable. For this reason, IGF1 deficiency has a central role in this whole process, as it is one of the most potent antiapoptotic, pro-survival, antioxidant, and cytoprotective factors known today (Adams et al. 2000; De Meyts and Whittaker 2002a; Gallagher and LeRoith 2010; Puche and Castilla-Cortázar 2012a, b). Once the plaque destabilises and ruptures, thrombosis may occur, and now vasodilators and vasoconstrictors play a pivotal role in the extent of the ischaemic injury. IGF1 is also known to have vasodilator actions (Gatenby and Kearney 2010). Furthermore, it has just been established that IGF1 deficiency renders mice resistant to angiotensin II, one of the most powerful arterial pressure coordinators, and also reduced cardiac contractility (González-Guerra et al. 2017a, b). Additionally, its cytoprotective and antiapoptotic actions could be helping during the ischaemic period until reperfusion.

4.3 4.3.1

IGF1 and the Heart Clinical Findings

Nowadays it is widely believed that IGF1 acts on the human CVS in direct or indirect ways: as an anabolic hormone, acting on early stages of foetal and embryonic heart development, and by augmenting erythropoiesis (Kling et al. 2006; Kadri et al. 2015) (indirectly augmenting volaemia), cardiac muscle mass (Muñoz et al. 2009; Ikeda et al. 2009), and contraction (Von Lewinski et al. 2003). In the myocardium, IGF1 exerts several effects, namely, metabolism (Aguirre et al. 2016), apoptosis (Kurmasheva and Houghton 2006), autophagy (Troncoso et al. 2013), ageing (Ungvari and Csiszar 2012a), fibrosis (Huynh et al. 2010; Ock et al. 2015; González-Guerra et al. 2017a, b), mitochondrial protection and energy

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expenditure efficacy (Conchillo et al. 2005; Pi et al. 2007; Puche et al. 2008b; Sádaba et al. 2016), and growth (De Meyts and Whittaker 2002b), among others. However, in humans, little is known about the physiology and anatomy of these actions. Still, it is well established that they have a direct and important role for the normal myocardium development and homeostasis. In this respect, and as collected in Table 1, several correlations have been made, e.g. IGF1 is negatively correlated with the risk for developing cardiovascular disease (CVD) (Ungvari and Csiszar 2012b). What is more, IGF1/IGFBP3 level alterations have been directly related to peripheral artery disease (Brevetti et al. 2008) and hypertension (Graham et al. 2008; Schutte et al. 2014; Fernández-Solà et al. 2015b). Findings so far suggest younger people to have low IGF1 related to CVD, MetS, dyslipidaemia, and hypercholesterolaemia (Juul et al. 2002a; Colangelo et al. 2004; Tong et al. 2005; Hypponen et al. 2008; Saydah et al. 2009; Sirbu et al. 2015), i.e. to be inversely correlated. Moreover, large epidemiological studies, like the Rotterdam and Framingham study, found an inverse correlation between IGF1 circulating levels and the risk for developing cardiac insufficiency (Vasan et al. 2003a; Bleumink et al. 2004), albeit some did not find any correlations (Ricketts et al. 2011). Also, IGF1 deficiency is associated with an increase of coronary artery disease (Spallarossa et al. 1996) and serves as a prognostic marker for ischaemic heart disease and coronary events (Kaplan et al. 2007). Accordingly, another study found that older patients with lower IGF1 (corrected to age GH/IGF1 decline) are at increased risk of ischaemic stroke and congestive heart failure (Vasan et al. 2003b). Moreover, in the context of acute heart infarct, IGF1 has shown to preserve cardiac function (Kotlyar et al. 2001), and, likewise, those with higher IGF1 values had the best prognosis (Lee et al. 1999), though not all found such (Hajsadeghi et al. 2011) as perpetrating controversy. Additionally, in a study undertaken in a small group of patients suffering from chronic heart failure, infusion of IGF1 improved haemodynamic parameters (Donath et al. 1998). All such correlations seem to have an age-dependent fashion. For the younger, a large study conducted in Chinese adolescents (1,642 patients of 12–19 years of age) revealed that both IGF1 and IGFBP3 concentrations were independently associated with waist circumference, fasting insulin, and haemoglobin concentrations in boys and systolic blood pressure, serum creatinine, fasting insulin, and haemoglobin concentrations in girls (Kong et al. 2011a). Additionally, IGF1 was also associated, in adolescent girls, with C-reactive protein concentration, and IGFBP3 was associated with fasting triglyceride concentration (Kong et al. 2011b). Within older populations, results are much more heterogeneous. For instance, a study of elder people screened 1,509 patients finding the opposite that high IGF1 levels positively correlate to MetS and dyslipidaemia (van Bunderen et al. 2013); this has been both supported (Andreassen et al. 2009; Yeap et al. 2010) and contradicted (Janssen et al. 1998; van Bunderen et al. 2010) by others. Other studies found low serum IGF1 concentrations, among the elderly, to be associated with higher prevalence of MetS, and/or sex differences among the elder (Maggio et al. 2006a, b; Jorn Schneider et al. 2008), or no correlations at all (Efstratiadis et al. 2006).

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Table 1 Clinical studies testing IGF1 levels under several conditions Reference/ sample size Design Favourable outcomes (Vasan et al. Cohort 2003b) n ¼ 717 (Brevetti et al. Case2008) n ¼ 185 control (Spallarossa Caseet al. 1996) control n ¼ 122 (Laughlin et al. Cohort 2004) n ¼ 1,185 (Schutte et al. Transversal 2014) n ¼ 86 (Schutte et al. Transversal 2014) n ¼ 101 (Sirbu et al. 2015) n ¼ 249 (FernándezSolà et al. 2015a) n ¼ 66 (Watanabe et al. 2010) n ¼ 205 (Janssen et al. 1998) n ¼ 218 (Lee et al. 1999) n ¼ 34

Condition tested

Outcome

Cardiac insufficiency Peripheral artery disease Coronary artery disease

Higher IGF1 levels correlated with less cardiac insufficiency Negative IGF1/IGFBP3 correlation

Ischaemic cardiac disease Arterial hypertension Carotid intima media

Association between low IGF1 and cardiovascular mortality Inverse correlation of IGF1 with systolic arterial pressure in black men IGF1 was inversely correlated with carotid intima media thickness in white men Low IGF1 associated with higher abnormality of the carotid intima media Less cardiac IGF1 expression in hypertensive patients

Casecontrol Casecontrol

Carotid intima media Arterial hypertension

Casecontrol

Cardiac insufficiency

Transversal

CVD and risk for CVD Acute myocardial infarction

Transversal

(Juul et al. Case2002b) n ¼ 605 control (Donath et al. Open-label 1998) n ¼ 8 Unfavourable/neutral outcomes (Andreassen Cohort et al. 2009) n ¼ 642 (Fischer et al. Case2004) n ¼ 187 control (Ricketts et al. Case2011) n ¼ 3,068 control (Kaplan et al. Case2007) n ¼ 1,258 control (Hajsadeghi Transversal et al. 2011) n ¼ 2,011

Low IGF1 significantly associated with coronary artery disease

Ischaemic cardiomyopathy Cardiac insufficiency

Inverse correlation of IGF1 with functional classification and mortality in cardiac insufficiency Low IGF1 correlated with an increment in the risk for or presence of CVD Lower IGF1 concentrations correlated with higher ventricular dysfunction following infarction Inverse correlation between IGF1 levels and ischaemic cardiomyopathy risk IGF1 infusion improved haemodynamic parameters

Cardiac insufficiency

Positive correlation between IGF1 levels and cardiac insufficiency incidence

Coronary artery disease CVD risk factors

Patients with coronary artery disease presented higher IGF1 concentrations No association between IGF1 levels and CVD risk factors were found No association between circulating IGF1 and CVD was found Total serum IGF1 concentration does not seem to be associated with short-term survival rates

CVD in the elderly Acute postmyocardial infarction prognosis

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Anthropometry and tissue metrics also appear to be correlated with IGF1. An interesting study conducted with 330 Japanese patients (age 51  8.6) (Kawachi 2005) showed body mass index (BMI) and plasma insulin to possess positive associations with circulating IGF1 and IGFBP3 ratios; subcutaneous adipose tissue correlated with IGF1. However, HDL was inversely associated with IGF1; and, lastly, blood pressure, total cholesterol, triglyceride, and visceral adipose tissue were positively associated with IGFBP3. By contrast, IGF1 and IGFBP3 were associated with carotid intima-media thickness independent of age, body mass index, blood pressure, and insulin, where insulin was also found to be associated with carotid intima-media thickness. In an attempt to explore these correlations, massive sequencing has led to the finding of several polymorphisms in Igf1 which have been linked to CVD or even to increased mortality following infarcts (Bleumink et al. 2005; Lin et al. 2013). Taken into account all of the above, it is logical to establish a cardioprotection activity for IGF1 (Ambler et al. 1993; Brownsey et al. 1997; Opgaard and Wang 2005; Castellano et al. 2009; Perkel et al. 2012; Troncoso et al. 2012; Touvron et al. 2012; Arcopinto et al. 2013; Cheng et al. 2015), in spite of the well-known mitochondrial, hepato-protection, and neuroprotection activities (Castilla-Cortazar et al. 1997a; Opgaard and Wang 2005; Pérez et al. 2008; Puche et al. 2008a, 2015; Castilla-Cortázar et al. 2011; Puche and Castilla-Cortázar 2012a, b; Ungvari and Csiszar 2012b; Troncoso et al. 2013, 2014a). In fact, several studies have proposed IGFBP7 (IGFBPrp1 or Mac25) as a useful marker for cardiac event prognosis, cardiac insufficiency, and diastolic dysfunction (Chugh et al. 2013; Motiwala et al. 2014; Gandhi et al. 2014). We strongly believe that the significant controversy held by cross-sectional and transversal studies is due, in part, to substantial bias introduced among them: population, age, sex, IGF1 titration methods, IGF1 regulation mechanisms not taken into account, multicentric studies introducing inter-hospital variations, and so on. It results apparent that mixed inclusion criteria can be blurring the results, as relations between MetS and CVD have been found, inasmuch as correlations of IGF1 levels and components of the MetS (Aguirre et al. 2016). In spite of this, it is difficult to reconcile the three of them (IGF1, MetS, and CVD), specially without introducing biases. To try and circumvent such handicap, a meta-analysis harbouring 14,938 patients concluded that overall higher and lower IGF1 levels (as opposed to physiological levels) positively correlate to increased risk for CVD in males, but no correlations where found for females (Jing et al. 2015). Still, it is important to mention that this analysis was region-restricted (western countries) and not age stratified. Also, when exploring IGF1 measurement methods, some doubts were raised. Most of the studies used immunosorbent assays to determine IGF1/IGFBP3 levels; however we could not trace the suppliers in order to determine if such assays did separate IGF1 from IGFBPs, if such methods discriminated IGF1 from IGF2, or even if the same antibodies among hospitals implicated in the multicentre studies were being used. Also, no information, generally, was supplied as how the extraction of blood/sera IGF1 was accomplished.

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Accordingly, it just seems appropriate to make certain assumptions based on the IGF1 decline with ageing (somatopause) and the increased risk for CVD as we age. Also, as MetS and T2D have been strictly related to low IGF1 levels (local or systemic), together with the somatopause, it could lead to a big protective deficit ultimately unleashing cardiac failure and/or embolism with haemorrhage (cardiac arrest or stroke). The current bias in the matter is that, not surprisingly, nearly all functional and biochemical studies performed so far have been conducted in animal, in vitro, and ex vivo models. In man, only IGF1 level correlations (cross-sectional or transversal cohorts) under cardiovascular conditions have been made, but no direct and empirical testing of IGF1 actions on this system has actually been done, logically due to human testing limitations. Even though IGF1/IGFBP3 ratio is commonly used as a rough estimate of IGF1 biologically active availability, nowadays it is known the tremendously complicated regulation that surrounds IGF1, not only its binding proteins and acid-labile subunit. Instead, additional complexity comes with regulation by proteases, receptor expression, turnover, pattern affinity (IR/IGF1R/hybrid receptors/IGF2R), and localisation; miRNAs; IGF1/IGF1R isoforms (alternative splicing); hepatic status; nutritional status, and somastotinergic tone; for what is known today (De Meyts and Whittaker 2002a). In this sense, we are far behind in determining IGF1-specific roles with correlations; instead experimental models offer more specific IGF1-mediated actions. Additionally, this complex regulatory mechanism could account for the missing consistency in these cohort studies, which do not take into account any of the factors aforementioned. Instead, new reliable methods to determine bio-useful IGF1 in sera should be attempted. In this regard, a very elegant method has been developed (Chen et al. 2003) which relies on IGF1R tyrosine trans-autophosphorylation, thus measuring receptor activation instead of free or total IGF1. However, it still lacks extensive testing and contrasting with conventional methods. Besides cross-sectional studies, a tremendous effort has been made in trying to unravel IGF1/IGF1R mechanistic and signalling mysteries, and so, the aim will be to marry human (ex vivo and primary cultures) and animal models in order to establish a plausible mechanism as why and how IGF1 is exerting such beneficial actions, potentially giving insight into new treatment approaches.

4.3.2

Basic, Animal, and Translational Studies

One of the most obvious IGF1 protection mechanisms is through the wellestablished antiapoptotic and survival effects, as discussed within an atherosclerosis context. Because it is known that several factors (hypoxia, ischaemia-reperfusion, oxidative stress) provoke myocyte death during the progression of heart failure (Chiong et al. 2011), one of the mechanisms by which IGF1 could be contributing to its protection is by acting to block apoptosis. When having a closer look into IGF1 actions in the heart, isoforms must be taking into account. Even though a specific profile pattern hasn’t yet been elucidated, some

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cues arise when it comes to damage and regeneration. It even seems a promising field as to avoid unwanted systemic effects of the hormone while focusing on tissuespecific effects in the heart like muscle hypertrophy, age- or disease-related atrophy prevention, and stem cell recruitment to injured or degenerating tissue (Rosenthal and Musarò 2002). Moreover, an interesting study found IGF1Ea to be overexpressed after myocardial infraction (twofold); however, it found a higher increase (above fivefold) in the IGF1Ec (MGF), whose actions seem to be IGF1Rindependent and to preferentially act through the Akt and not the MAPK pathway, even being expressed in different temporal spaces following infarction (days to weeks, coinciding with cardiac remodelling timing) (Stavropoulou and Halapas 2009). Further this is sustained by another work which even proved with precision that the E domain of the MGF alone elicited cardiac protection against myocardial infarction IGF1R independently and nucleus-mediated (Mavrommatis et al. 2013). Nonetheless, this could be consistent with IGF1/2 internalising actions of the IGF2R, as cardiac microdomains are in direct apposition to the nucleus and thus acting over intracellular targets or G proteins discussed for IGF2R signalling. Otherwise, perhaps such actions are due to ligand-binding loci within the receptor being different for IGF1Ea and IGF1Eb; thus antibodies α-IGF1R may be blocking one site and not the other. Moreover, it was proven that cardiac-restricted transgene expression of the mIGF1 isoform exerted a protective effect following drug-induced cardiac infarct through enhancement of sirtuin 1 expression (Vinciguerra et al. 2009). In addition to IGF1 isoforms, further complexity comes from micro-RNA regulation of IGF1. A group elegantly suggested that following ischaemia/reperfusion injury, there was an elevation in miR-29a and Let7 micro-RNA expression which would halt IGF1 expression (Wang et al. 2015b), hence blocking its antiapoptotic actions. IGF1 is the most potent protein synthesis, protein degradation inhibitor, and cell growth-promoting factor known (McMahon et al. 2010). Owing to this fact, IGF1 and IGF1R have been found upregulated during differentiation of skeletal muscle cells, where selective overexpression of IGF1 in cardiomyocytes or skeletal muscle cells resulted in increased protein content and size (Glass 2005). It was shown that, in mice cardiomyocytes, the overexpression of IGF1 produces physiological hypertrophy by protein translation rather than pathologically altering gene expression (McMullen et al. 2004). Parallel to this, Igf1r deletion resulted in normal heart growth although resistant to exercise-induced hypertrophy (Kim et al. 2008). But, when instead the hepatic Igf1 gene was knocked out, larger ventricular dimensions were observed together with a worse post-infarction remodelling (Scharin Täng et al. 2012). More interestingly, transgenic mice overexpressing IGF1 in cardiac myocytes produced hypertrophy and exerted better cardiac function in the short term, however turning to heart failure in the long term (Delaughter et al. 1999). It is nevertheless consistent with this group’s line of reasoning, which believes that IGF1 should never be exploited for its beneficial actions. IGF1 is still a hormone and, alike other hormones (insulin, thyroid hormones, glucocorticoids, sex hormones, etc.), should be kept within physiological ranges to avoid unwanted effects. Also recall that MetS and T2D leading to atherosclerosis and CVD all frame within an IGF1 physiological

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deficiency. For this reason, IGF1 should be administered, in our opinion, only when a deficiency has been identified and at low doses, which restores physiological levels and possesses beneficial effects (Conchillo et al. 2005; Puche et al. 2008a, 2015; Garcia-Fernandez et al. 2011; Castilla-Cortazar et al. 2014; Castilla-Cortázar et al. 2015a, b; Ita et al. 2015; Lara-Diaz et al. 2017). This hypothesis seems to be sustained by the abovementioned meta-analysis covering 14,938 patients, which found overall predisposition to CVD when IGF1 is both low and high (Jing et al. 2015). Autophagy, a process that has lately gained a tremendous attention, has been proven to be either downregulated or upregulated under certain stressors [starvation, absence of growth signals, oxidative stress, pro-inflammatory signals, hypoxia, and endoplasmic reticulum stress (Choi et al. 2013)] and specifically under some cardiac pathological conditions, namely, remodelling, elevated mechanical afterload, chronic ischaemia, and ischaemia/reperfusion injury (Nemchenko et al. 2011; Lavandero et al. 2013). It is believed that IGF1 confers protection against autophagy by negatively regulating it through mTORC1 (Jia et al. 2006; Bitto et al. 2010), as well as by increasing ATP levels, mitochondrial metabolism, Ca2+ dynamics regulation, and oxygen consumption (Troncoso et al. 2012; Shaikh et al. 2016). IGF1 has also proven to be effective under nutrient-deprivation stress in the heart by this same mechanism (Troncoso et al. 2012, 2013). It is worth highlighting that autophagy is an important process for organelle, protein, structure, and cell (apoptosis) turnover. Hence, this is one more situation where IGF1 should be kept at physiological ranges, as we would want to protect the cell from over-engaging autophagy (apoptosis) and, also, from poor performance (low turnover leading to cell malfunction). As abovementioned, IGF1R preferentially activates Akt1 (controlling growth), whereas the IR prefers Akt2 (controlling metabolism), and hybrid receptors could activate both of them, to which insulin only binds at supraphysiological levels. Such hybrid receptor has been found expressed in the skeletal muscle, heart, coronary artery smooth muscle cells, adipose tissue, fibroblasts, spleen, red and white blood cells, and placenta (Pierre-Eugene et al. 2012), thus suggesting a direct metabolic role played by IGF1 in all such tissues. Recall section in metabolic regulation by IGF1. Interestingly, this hybrid receptor is usually upregulated in the skeletal muscle of obese patients, presumably due to hyperinsulinaemia (receptor sensitisation), hence suggesting that IGF1 might be used to rescue insulin’s signal under such conditions (Federici et al. 1998). Correlations between IGF1 levels and glucose intolerance, T2D, abdominal obesity, and atherogenic dyslipidaemia have been found (Puche and Castilla-Cortázar 2012a, b). Treatment with rhIGF1 of T1D and T2D enhanced protein and glucose metabolism and improved glucose tolerance, hyperinsulinaemia, and hypertriglyceridaemia (Federici et al. 1998; Simpson et al. 2004). It also improved insulin sensitivity, increased oxidative and non-oxidative metabolism, as well as augmented FFA uptake by the skeletal and cardiac muscle (Moses 2005). In a metabolic dysregulation frame, as aforementioned, an IGF1 deficiency and/or signal impairment occurs which leads to mitochondrial dysfunction, intracellular Ca2+ deregulation, and abnormal insulin signalling (Marsh and Davidoff 2012; Troncoso et al. 2014a). Moreover, Igf1 deletion led to reduced

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myocardial creatine, altering energetic homeostasis (Täng et al. 2012). Conversely, IGF1 overexpression in a transgenic model halted the deleterious effects of high-fat feeding (Zhang et al. 2012; Troncoso et al. 2014a), sustaining the idea of a role of IGF1 in restoring insulin’s signal, still by a not well-understood mechanism. It is now widely accepted that ageing can be regarded as an IGF1 deficiency condition, but whether the decline of the GH/IGF1 axis prolongs lifespan or not still remains a controversial issue (Puche and Castilla-Cortázar 2012a, b; Ungvari and Csiszar 2012a). However, it has been established that as the GH/IGF1 declines with age, it correlates with a decline in cardiovascular function and progression of CVD. As previously mentioned, IGF1 levels negatively correlate with an increase in the risk for CVD, stroke, and T2D. An illustration of the above can be observed in untreated Laron patients who show reduced life expectancy due to cardiovascular events (Guevara-Aguirre et al. 2011). These patients show reduced cardiac dimensions and output at rest, alterations reverted by IGF1 substitutive therapy (Scheinowitz et al. 2009). Extensive research has been performed in order to understand the role of IGF1 in progenitor cardiac cells. Today, studies rise light over this events and have demonstrated that cardiomyocytes do replicate (Anversa et al. 2013; Senyo et al. 2013; Boström and Frisén 2013; Garbern and Lee 2013), although with high controversy. This controversy has now been further increased, not due to sceptical thinking towards cardiac cell regeneration, but due to the recent discovery that cardiac c-Kit+ cells are not progenitor cells, but endothelial cells (van Berlo et al. 2014; Sultana et al. 2015). The c-Kit marker is generally used for progenitor cells in other tissues; however, it seems that there is debate in this field. Because of this, and because the vast majority of studies performed to test progenitor cell under a myriad of circumstances were based upon c-Kit marker, all hypotheses are now being challenged. Nevertheless, certain studies did prove the existence of cell regeneration with alternative techniques; however they are found to replicate from pre-existing cells and not from a progenitor cell pool (Senyo et al. 2013). But, interestingly, when injury or pressure is applied, then progenitor cells do account for new cells (Hsieh et al. 2007), being in line with the IGF1 secretion pattern aforementioned. Most of cardiac regenerative approaches were done by in vitro expansion, but data indicate that transplanted cells do not survive in the host for long (Hsieh et al. 2007). Intriguingly, beneficial actions were observed when IGF1 was administered intra-myocardially, such as cell migration, proliferation, and survival (Linke et al. 2005; Kawaguchi et al. 2010). These observations pinpoint a paracrine mechanism for the benefits observed in such approaches (Loffredo et al. 2011). For this, several candidate molecules have been found (Segers and Lee 2010), being IGF1 of vital importance for c-Kit+ cardiac cells (whether they are progenitor or endothelial cells) (Yu et al. 2009). Cocultured cardiac cells expressing c-Kit have shown to secrete IGF1, which improved cardiomyocyte survival and contractility (Kawaguchi et al. 2010), previously thought to be a progenitor response. Moreover, in c-Kit+ cells derived from human hearts, when expressing IGF1R, an augmented telomerase activity, proliferation, cardiac “differentiation” (as measured byGATA4, Nkx2.5, α-SA, L-type Ca2+ channels, α-subunit of voltage-gated Na + channels type V, and ryanodine receptor mRNA transcription

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increase), and decreased apoptosis were observed, whereas, in its absence, senescence and apoptosis were observed at higher ratios (D’Amario et al. 2011). In mice and rat models of myocardial infarction, the direct co-administration of IGF1 and hepatocyte growth factor or IGF1 nanofibers promoted c-Kit+ cell activation in vivo leading to cardiomyogenesis, decreased fibrosis, and reduced hypertrophy (Urbanek 2005; Davis et al. 2006a; Rota et al. 2008; Padin-Iruegas et al. 2009). However, we have to be cautious when affirming such hypothesis or regard them as pre-existing-cell regeneration and not progenitor-pool-derived cells. Signalling pathways for such mechanisms have not been solved so far, yet activated Akt, decreased activation of caspase-3, and increased expression of cardiac troponin I have been proposed (Davis et al. 2006b). As well, a general upregulation of protein mRNA content in c-Kit+ cells after IGF1 and hepatocyte growth factor administration upon infarction was found (Genead et al. 2012), suggesting the implication of mTORC1 (as a protein synthesis activator). Most of these actions are thought to be mediated by Akt activation (Wetterau et al. 2003) and Ca2+ oscillations (Ferreira-Martins et al. 2009) triggered by PLC activation, as abovedescribed. With regard to fibrosis, an intimate relationship between fibrosis and left ventricular rigidity with CVD and augmented risk for CVD was found, as Palmiero and colleagues have very well recently revised (Palmiero et al. 2015). As well, it was observed in rats that fibrosis modulation by IGF1 (fibroblast-mediated) seems to be age-dependent (Diaz-Araya et al. 2003), consistent with the fact that IGF1 declines as we age. Apparently, IGF1 is produced by cardiac fibroblasts as an autocrine molecule for the production of collagen and as a paracrine hormone, thereby acting in cardiomyocyte signalling protein translation with a concomitant hypertrophy (Horio et al. 2005). Also, it has been discovered that fibroblasts subjected to physical stretching produce larger quantities of IGF1, including a rise in mRNA expression of auricular natriuretic peptide in ventricular myocytes (Hu et al. 2007), both of which seem to possess a beneficial action in the heart. In this sense, a complex relationship establishes between the IGF1 system and the extracellular matrix. Additionally, an association was made between IGF1, metalloproteinases, and risk factors for CVD (Sesso and Franco 2010). Some IGFBPs have as a target to get “stuck” in the extracellular matrix (e.g. IGFBP8, also called connective tissue growth factor) where they can operate as an IGF1 pool, which may explain such relationship. Conversely, IGF1 also acts by modulating the extracellular matrix dynamics, as to regulate transcription of metalloproteinases and tissue inhibitor of MMPs (TIMPs, their regulators) (Fowlkes et al. 2004). Moreover, it has been previously described that the improper hepatic (Lara-Diaz et al. 2017) and testicular (Castilla-Cortázar et al. 2015c) architecture (in the sense of cell organisation and extracellular matrix formation) results from partial IGF1 deprivation in mice and has very recently been also characterised for cardiac tissue (González-Guerra et al. 2017a, b). That same study associated IGF1 deficiency to a significant reduction in heart contractibility, expressed as the dP/dt quotient, angiotensin II resistance, and fibrosis (interstitial and perivascular) (González-Guerra et al. 2017a, b). In addition, a dramatic reduction in the expression of genes coding for proteins involved in calcium dynamics as well as regulatory myosin proteins, α2-actin, and natriuretic peptides was observed.

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Remarkably, in this study, IGF1 replacement therapy returned haemodynamic values to normal and reverted fibrosis when compared to controls, excluding the expression of several altered genes. It is widely known that alterations in extracellular matrix architecture and fibroblast death are crucial in the establishment of cardiac pathology. In the same line, the abrupt rise in apoptosis and necrosis of cardiac fibroblasts following ischaemia/reperfusion can be partially inhibited by IGF1 (Vivar et al. 2012). IGF1 has been found to have a role in migration, organisation, and function of cardiac fibroblasts, hence having a decisive job in cardiac fibrosis (Kanekar et al. 2000).

4.4

IGF1 Deficiency and Stroke

Global burden of stroke and classic risk factors have been recently and thoroughly studied (Feigin et al. 2016), but the emerging IGF1 molecular role as a biomarker, already associated with cardiovascular risk factors and atherosclerosis (Tang et al. 2014), has not yet been extensively studied. What it is known is that IGFs are also (besides hepatic-derived) synthesised by the brain and are involved in foetal brain growth, development, myelination, and brain plasticity (as indexed by neurogenesis) (Schwab et al. 1997; Aberg 2010). In addition, IGF1 also exerts neuroprotective effects in both white and grey matter under different detrimental conditions. In clinical studies, low IGF1 and IGFBP3 serum concentrations have been linked to arteriosclerosis and an increased risk of ischaemic stroke (Johnsen et al. 2005; Kawachi 2005; Sirbu et al. 2015), as previously mentioned. Moreover, IGF1 levels immediately after an acute-phase stroke and after 3 months both positively correlate with improvement according to the modified Rankin scale (Aberg et al. 2011). A 100-patient study revealed no correlation between IGF1 or IGFBP3 and lesion volume. Instead, only an association was found between IGFBP3 and a worse outcome (according to the modified Rankin scale) after a year follow-up (Ebinger et al. 2015), suggesting a plausible marker for stroke outcome. It is important to note that this study was age (mean age 64  15) and population (in Berlin only) biased, which also found correlations between age, IGF1, and IGFBP3 levels, with clinical outcome. Basic and translational studies ascribe neuroprotective effects to IGF1, IGFBP3, and GH (Aberg et al. 2011; Ebinger et al. 2015). What is more, IGF1 has been shown to protect against stroke in rats when administered intracerebro-ventricularly (Liu et al. 2001). However, this invasive method of administration is not practical for humans who may require treatment for stroke. Intranasal delivery instead offers a non-invasive method of bypassing the blood-brain barrier to deliver IGF1 and other neurotrophic factors to the brain (Liu et al. 2001). Also, hepatic-derived serum IGF1 has recently been shown to have the unexpected ability to modulate normal brain function as well as brain response to injury (Schäbitz et al. 2001). Alike many growth factors, IGFs are present in the brain, are involved in brain development, and

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are reactivated after brain insults (Schäbitz et al. 2001). In addition, brain injury triggers the expression of IGFs, IGF1R, and IGFBPs (Schäbitz et al. 2001). Increased expression of IGFs has also been observed within cerebral regions bearing neuronal damage caused by experimental hypoxia (Schwab et al. 1997). Furthermore, the expression of mRNAs coding for IGF1, IGFBP2, and IGFBP3 is augmented in response to unilateral ischaemia in experimental models (Schwab et al. 1997). Neuronal damage caused by ischaemic brain injury is associated with increased apoptosis (Chung et al. 2007). Consistently, IGF1 exposure promotes neuronal defence and survival against ischaemic insult by inhibiting apoptotic processes (Chung et al. 2007).

4.5

IGF1 Treatment: Future and Limitations

The FDA accepts the use of recombinant human IGF1 (rhIGF-1), mecasermin/ Increlex™ (rhIGF1) or mecasermin rinfabate/iPlex™ (equimolar rhIGF1/ IGFBP3), for treatment of severe primary IGF1 deficiency. A number of clinical trials have tested IGF1 under several circumstances (Table 2), such as growth hormone insensitivity, idiopathic short stature, paediatric severe burns, osteopenia/ osteoporosis linked to anorexia nervosa and severe bone fractures, and metabolic disorders (Herndon et al. 1999; Debroy et al. 1999; Jeschke et al. 2000a, 2001, Clemmons et al. 2000, 2005; Spies et al. 2002; Boonen et al. 2002; Grinspoon et al. 2002; Rosenbloom 2009). Other conditions that have been considered for IGF1 therapy, based upon the ubiquitous tissue-building properties of IGF1, include chronic liver disease, cystic fibrosis, wound healing, acquired immunodeficiency syndrome, muscle wasting, Crohn’s disease, Werner syndrome, X-linked severe combined immunodeficiency, Alzheimer’s disease, amyotrophic lateral sclerosis, hearing loss prevention, spinal cord injury, cardiovascular protection, and prevention of retinopathy of prematurity (Spies et al. 2002; Rosenbloom 2009). Despite clinical benefits, controversy of long-term IGF1 administration safety persists. Some rare severe adverse effects from long-term rhIGF1 treatment have been reported including neoplastic formation, cataract, renal hypertrophy, and facial coarsening of features (Ebeling et al. 1993; Backeljauw et al. 2001; Bright et al. 2009; Puche and Castilla-Cortázar 2012a, b; Pekic and Popovic 2013). Nevertheless, such negative effects were transitory, easily handled, and tolerated, with treatment discontinuation not being necessary. Mild side effects reported ranged from transient pain and lipohypertrophy at injection site, headache (Ranke et al. 1999), papilloedema (related to cranial hypertension), facial nerve paralysis (Quattrin et al. 1997; Clemmons et al. 2005), lymphoid tissue growth (specially acromegaly and tonsillar hypertrophy), renal enlargement (with normal kidney function), and incremented hair growth. Symptoms, however, did not prevail after lowering dosage (Ranke et al. 1999). Exercise is one of the most potent IGF1 releasers into the bloodstream. Single bouts of moderate/high intensity significantly raise IGF1 levels in plasma (Berg and

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Table 2 IGF1 treatment clinical studies Condition Severe primary IGF1 deficiency due to GHI

Idiopathic short stature (ISS) children GH-IGF1 response in GH deficiency and ISS children

Paediatric severe burns

Severely burned children

Osteopenia/osteoporosis in patients with recent hip fracture

Osteopenia/osteoporosis in patients with anorexia nervosa

Myotonic dystrophy type 1

Results/side effects Treatment with rhIGF1 stimulates linear growth in children with severe IGF1 deficiency due to GHI. Adverse events (hypoglycaemia) are common but are rarely of sufficient severity to interrupt or modify treatment In ISS children who do not respond to GH treatment, IGF1 therapy is a theoretical option ISS subjects required higher GH doses than GH-deficient patients in the IGF2T (but not IGF0T) arm; IGF1-based GH dosing is clinically feasible in both GH deficiency and ISS patients IGF1/IGFBP3 at doses of 1 to 4 mg/kg/day attenuates catabolism in catabolic burned children with negligible clinical side effects IGF1/IGFBP3 showed a decrease in IL-1β and TNF-α followed by a decrease in type I acute phase proteins Patients treated with 1 mg/kg/ day rhIGF1/IGFBP3 regained a substantial portion of their femoral bone mass. At 2-month the treatment is feasible, safe, and well tolerated Osteopenic women with anorexia nervosa treated with rhIGF1 and oral contraceptive showed more beneficial changes in bone density, compared with patients not treated with rhIGF1 or treated with oral contraceptive alone rhIGF1/rhIGFBP3 was associated with increased lean body mass and improvements in metabolism, but not with increased muscle strength or function

Clinical status FDA approved in 2005 Clinical trial, predominantly open-label

References (Kemp 2009)

Insufficient evidence, or clinical trials, data are lacking regarding efficacy and safety Multicentre open-label, randomised controlled, clinical trial, 2-year follow-up

(Cohen et al. 2008)

Clinical trial

(Herndon et al. 1999; Debroy et al. 1999)

Clinical trial

(Jeschke et al. 2000b)

Randomised, doubleblind, placebo-controlled pilot study

(Boonen et al. 2002)

Blinded placebo controlled trial

(Grinspoon et al. 2002)

Clinical trial

(Debroy et al. 1999)

(Cohen et al. 2010)

(continued)

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Table 2 (continued) Condition Type 1 DM

Results/side effects IGF1/IGFBP3 is biologically active on carbohydrate metabolism, as measured by a decrease in insulin requirements in patients with type 1 diabetes

Clinical status Randomised, crossover, double-blind, placebocontrolled trial

References (Clemmons et al. 2000)

rhIGF1 human recombinant insulin growth factor 1, GH growth hormone, IGFBP3 insulin growth factor-binding protein 3, ISS idiopathic short stature

Bang 2004). Such rapid increase might be due to either IGF1 release from stores or to proteolytic cleavage of IGFBP3. Furthermore, during exercise pH drops negatively affecting IGFBP affinity for IGF1/2. Muscle tissue has been found to be the major contributor to this rise in IGF1 (Brahm et al. 1997). To date, exercise is the best option when it comes to treating metabolic alterations (MetS, T2D, atherosclerosis, CVD, etc.), owing such effects to fat burning, cardiovascular toning, neuroendocrine system activation, and chronic inflammation grade lowering. Because exercise is one of the most potent IGF1 synthesis/freeing mechanisms, it seems logical to correlate classical exercise beneficial actions and IGF1 and establish IGF1 as a target for future options in the multifactorial treatment for these conditions. The abovementioned complications rose fear and controversy among the scientific community towards IGF1 treatment safety. The problem often perceived in these trials is the dosage used. These are normally over the dosage needed for restoring the normal physiological levels of the hormone. Dosages ranged from 80 μg to 4 mg/kg/day, for a wide spectrum of lengths (weeks to months) and routes of administration. Previous experimental data demonstrated that short cycles (10, 14, 21, or 30 days) of very low subcutaneous doses (20 μg/kg/day) effectively restored physiological serum values of the molecule. Such dosage has not reported any of the adverse effects aforementioned (Puche and Castilla-Cortázar 2012a, b). We are conscious of the limitations animal models bear. However, a clinical trial assessed IGF1 and liver function under cirrhosis with this same dosage (20 μg/kg/day), where no side effects were reported and liver function greatly increased (Conchillo et al. 2005). Our firm opinion is that problems with IGF1 treatment are solely a matter of dosage. If the hormone is sustained at a physiological level, no biological consequences should arise. If such levels are exceeded, as a growth factor and alike every other hormone, unwanted effects will appear. Fear towards tumorigenesis and IGF1 should wear off when a physiological level is never beaten, as IGF1 is a cytoprotective and antioxidant factor, not a tumorigenic agent. Nevertheless, to overcome such fear, tumour marker tests should be performed prior to treatment initiation. Not surprisingly, none of the abovementioned trials screened for such markers, potentially discarding any ongoing or incipient tumorigenic process. Clearly, IGF1 as a growth factor would hasten any tumorigenic activity if present. IGF1, as it is the case with other hormonal substitutive therapies (thyroid hormone or

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insulin), must never be frivolously applied without first confirming its deficiency (local, central, or systemic). Meticulous supervision during treatment ought to be carried out to guarantee a safe outcome.

5 Conclusions 1. At the initiation of metabolic deregulation by overfeeding, IGF1 is decreased/ inhibited. 2. Such deficiency seems to be intimately related to the onset of MetS, establishment of vascular derangements leading to atherosclerosis. 3. IGF1 has a potent role in the myocardium, where apparently it modulates autophagy, cardiac progenitor differentiation, and extracellular matrix dynamism and also confers cardioprotection. It also plays a definitive part in cerebrovascular and myocardial accidents, where its deficiency seems to render these organs vulnerable to oxidative and apoptotic/necrotic damage. 4. Several human cohort correlations, together with experimental data, seem to confirm all of these, albeit with controversy, which might, in part, be given by experimental design leading to blurred result interpretation. 5. Taking all into account, an urgent call for further experimentation is needed as to definitely clarify IGF1 role in these systems and potentially give rise to new therapeutic options. Acknowledgements We would like to give a very special thanks to MSc Irene Martín del Estal for her support and to Oliver Gómez Gutierrez, senior medical student at Tecnológico de Monterrey, for his invaluable contribution in figure editing. Disclosure Statement Authors declare to have no competing or financial interests. Financial Information This research did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.

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Rev Physiol Biochem Pharmacol (2018) 175: 47–70 DOI: 10.1007/112_2018_9 © Springer International Publishing AG, part of Springer Nature 2018 Published online: 27 April 2018

Potential of Cationic Liposomes as Adjuvants/Delivery Systems for Tuberculosis Subunit Vaccines Farzad Khademi, Ramezan Ali Taheri, Amir Abbas Momtazi-Borojeni, Gholamreza Farnoosh, Thomas P. Johnston, and Amirhossein Sahebkar Contents 1 2 3 4 5 6 7 8

TB Infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . BCG and the Advantages and Disadvantages of Current TB Vaccines . . . . . . . . . . . . . . . . . . . Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of Cationic Liposomes as TB Adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DDA-Based Adjuvants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Role of Cationic Liposomes as a TB Delivery System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DDA-Based TB Delivery System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DOTAP-Based TB Delivery System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

F. Khademi Department of Microbiology, School of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran R. A. Taheri (*) Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran e-mail: [email protected] A. A. Momtazi-Borojeni Nanotechnology Research Center, Student Research Committee, Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran G. Farnoosh Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran T. P. Johnston Division of Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, MO, USA A. Sahebkar (*) Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran e-mail: [email protected]; [email protected]; [email protected] edu.au

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9 DC-Chol-Based TB Delivery System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Challenges of Cationic Liposomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Abstract The weakness of the BCG vaccine and its highly variable protective efficacy in controlling tuberculosis (TB) in different age groups as well as in different geographic areas has led to intense efforts towards the development and design of novel vaccines. Currently, there are several strategies to develop novel TB vaccines. Each strategy has its advantages and disadvantages. However, the most important of these strategies is the development of subunit vaccines. In recent years, the use of cationic liposome-based vaccines has been considered due to their capacity to elicit strong humoral and cellular immune responses against TB infections. In this review, we aim to evaluate the potential for cationic liposomes to be used as adjuvants/delivery systems for eliciting immune responses against TB subunit vaccines. The present review shows that cationic liposomes have extensive applications either as adjuvants or delivery systems, to promote immune responses against Mycobacterium tuberculosis (Mtb) subunit vaccines. To overcome several limitations of these particles, they were used in combination with other immunostimulatory factors such as TDB, MPL, TDM, and Poly I:C. Cationic liposomes can provide long-term storage of subunit TB vaccines at the injection site, confer strong electrostatic interactions with APCs, potentiate both humoral and cellular (CD4 and CD8) immune responses, and induce a strong memory response by the immune system. Therefore, cationic liposomes can increase the potential of different TB subunit vaccines by serving as adjuvants/delivery systems. These properties suggest the use of cationic liposomes to produce an efficient vaccine against TB infections. Keywords Adjuvant · Cationic liposome · Delivery system · M. tuberculosis · Subunit vaccine

1 TB Infection Mycobacterium tuberculosis (Mtb) bacterium is a rod-shaped intracellular organism that causes an infectious disease called tuberculosis (TB). Today, TB, as a global public health problem, has infected, although asymptomatically, two billion people worldwide. The bacterium is responsible for nine million new TB cases each year and causes two million deaths. The organism spreads between individuals by coughing or sneezing through the upper respiratory tract, which results in air-borne droplets or dried sputum; both, of which, are contagious. Patients with the active form of TB are the source of Mtb transmission to healthy people. After inhalation of contaminated air-borne droplets of Mtb and migration of the Mtb to the human lung, they are phagocytosed by inactivated alveolar macrophages. Antigen presenting cells (APCs) such as dendritic cells (DCs), alveolar macrophages, and pulmonary epithelial cells are a key part of immunity and engulfment of the

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bacterium acts like a bridge between the innate and adaptive immune response. This process ultimately leads to activation of various cell types in the lung by inducing an inflammatory response. The activated innate immune cells, which include neutrophils, blood monocytes, natural killer (NK) cells and the complement system, are recruited to eliminate the pathogen through recognition of pathogen-associated molecular patterns (PAMPs), mycobacterial cell wall components on the bacteria, by receptors, pattern recognition receptors (PRRs), and specifically by the toll-like receptors (TLRs) on APCs. The innate immune response contributes to the defense against Mtb by activation of infected macrophages or by destruction of Mtb-infected macrophages, intracellular bacterial killing, and the recruitment of adaptive immune cells by proinflammatory cytokines. However, the innate immune response is not entirely sufficient and, thus, the adaptive immune response is required at the site of infection. In the alveoli, TB bacilli can actively modulate the activity of inactivated alveolar macrophages using a variety of different mechanisms. One such mechanism includes inhibiting the acidification of the phagosome and its fusion with the lysosome and its resistance to effector molecules, such that the bacterium begins to replicate until there is rupture of the macrophage, with subsequent release into the cytosol. Rapid bacterial growth during the early phase of infection leads to the presence of bacterial antigens and the induction of cell-mediated immunity (CMI) by DC cells in the lymph nodes. Activated T-cells return to the site of infection and serve as the main immune response in controlling bacterial replication, without killing the bacteria, in the solid granuloma, or tubercle. The TB granuloma contains inactive bacteria, necrotic and infected macrophages, and several phenotypes of macrophages (epithelioid cells, multi-nucleated giant cells, and foamy macrophages), DCs, neutrophils, NK cells, B-cells, CD4+, and CD8+ T –cells. A fibrous shell occurs at the latent tuberculosis infection (LTBI) phase and helps to keep bacteria from spreading. Reactivation to active TB disease, in 10% of latentlyinfected people, especially immunocompromised individuals such as HIV and AIDS-positive patients, occurs due to deficiency in the host’s immune system and imbalance between the immune response and the pathogen. Impairment of immune response leads to the formation of a caseous granuloma with a liquified center. As a result, the bacterium begins to multiply uncontrollably and granulomas are destroyed, which leads to the release of virulent bacilli in the lungs, the body, or the environment (active TB) (Fig. 1) (Andersen 2007; Andersen and Kaufmann 2014; Khademi et al. 2016, 2017a, b; Li et al. 2011; Ottenhoff and Kaufmann 2012; Pitt et al. 2013; Wang et al. 2013).

2 BCG and the Advantages and Disadvantages of Current TB Vaccines It has been proven that to reduce the global burden of TB, as well as the morbidity and mortality rate of TB infection, vaccination is one of the most successful approaches (Andersen and Kaufmann 2014; Girard et al. 2005). Bacillus

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Infected macrophage

Infected foamy macrophage

Infected giant macrophage

Necrotic cells and caseum

Granuloma

Fig. 1 The TB granuloma. After infection by the aerosol containing M. tuberculosis (Mtb), Mtb is first phagocytized by alveolar macrophages of the lungs. Following phagocytosis, Mtb provides a microenvironment within endosomal compartments of these macrophages where it can replicate and disrupt natural macrophage microbicidal mechanisms. Other macrophages and innate immune cells accumulate around these initial sites of Mtb replication, forming the TB granuloma. The center of the granuloma, where the majority of Mtb bacilli are presented, undergoes considerable cell necrosis that builds up necrotic cell debris called caseum, leading to collapse of the granuloma and, thereby, releasing virulent bacilli to infect new host tissues. Around the central necrotic region, granuloma macrophages can fuse to form multi-nucleated giant cells, or alternatively differentiate into foam cells subsequent to the accumulation of lipids

Calmette–Guérin (BCG), a viable attenuated strain of Mycobacterium bovis, was developed in 1921 and millions of people around the world have been vaccinated with it. To date, BCG is the only commercially-approved vaccine against TB infection (Girard et al. 2005). However, most studies have shown that the protective efficacy of BCG varies from excellent to no protection at all in different age groups, as well as in different geographic areas (Girard et al. 2005). Studies have proven that the efficacy of BCG vaccination against severe forms of the disease, meningitis, and disseminated TB, in young children is high (46–100%) (Girard et al. 2005). Nevertheless, vaccine efficacy is inconsistent (0–80%) against pulmonary TB in adolescents and adults and with limited effectiveness upon reactivation of the dormant form of a TB infection (Bottai et al. 2015; Girard et al. 2005; Kong et al. 2014). On the other hand, lack of safety in immunocompromised patients, such as HIV-positive individuals, and decreased vaccine efficacy with advancing age (due to inadequate immunological memory) are additional problems for the BCG vaccine (Nor and

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Musa 2004). Therefore, it is essential that the research community develop safe, stable, effective, and inexpensive vaccines for BCG and improve its effectiveness by using additional different vaccines to augment the effectiveness of the BCG vaccine (Nor and Musa 2004). Most successful TB vaccine candidates in clinical trials are divided into two categories: (1) whole mycobacterial vaccines (live and killed vaccines) and (2) non-living vaccines (subunit vaccines and DNA-based vaccines). Live mycobacterial vaccines such as recombinant BCG (rBCG) (VPM1002, phase IIa) and the rMtb deletion mutant (MTBVAC, phase I) are preventative vaccines that are administrated as “pre-exposure” vaccines (before TB infection) in newborns and adolescents. These types of vaccines work through the overexpression of TB antigens or by removal of virulent genes in order to attenuate M. tuberculosis (Andersen 2007; Andersen and Kaufmann 2014; Checkley and McShane 2011; Kaufmann 2013). Despite some advantages, the possibility of disseminated disease in HIV-positive patients and interference with the tuberculin skin test (i.e., the Mantoux skin test) are the two main disadvantages of rBCG vaccines (Nor and Musa 2004). Killed mycobacterial vaccines such as the RUTI (derived from fragmented M. tuberculosis, phase I) killed M. vaccae (phase III), and M. indicus pranii (MIP) (phase III) are therapeutic vaccines and administered against active TB infections and to patients with drug resistant strains of M. tuberculosis (Andersen 2007; Andersen and Kaufmann 2014; Checkley and McShane 2011; Kaufmann 2013). However, the protective efficacy of these type of vaccines is no better than BCG (Nor and Musa 2004). Non-living, DNA-based vaccines are DNA plasmids containing mycobacterial genes, which can induce both humoral and cellular (CD4 and CD8) immune responses against TB infections (Nor and Musa 2004). Some advantages of DNA-based vaccines include increased safety for immunocompromised individuals, ease of vaccine manipulation and administration, and better storage and transport properties, however, there is no DNA-based vaccine in clinical trials at present (Nor and Musa 2004). This may be due to the insertion into the host genome and the risk of autoimmune disease (Nor and Musa 2004). Today, most TB vaccines in the development pipeline and in clinical trials belong to the subunit protein-based vaccines. Immunogenic antigens or lipid or carbohydrate components of the bacterium are used to create subunit vaccines (Andersen and Kaufmann 2014). Safety and ease of production are the two main advantages of subunit proteins (Checkley and McShane 2011; Nor and Musa 2004). Non-living vaccines, unlike mycobacterial whole-cell vaccines, are not immunostimulatory molecules due to their synthetic nature, and are therefore not able to induce maturation of dendritic cells to stimulate the appropriate immune response and, hence, immunity (Karimi et al. 2016). Non-living vaccines are divided into two categories, (1) viral-based vaccines, and (2) adjuvant-based vaccines (Andersen and Kaufmann 2014). Viral-based, non-living subunit vaccines include Ad5Ag85A (antigen: Ag85A, carrier: Adenovirus 5 vector, phase I), Ad35/MVA85A (antigen: Ag85A, Ag85B and TB10.4, carrier: Adenovirus 35 and modified vaccinia Ankara vector, phase I), Ad35/AERAS-402 (antigen: Ag85A, Ag85B and TB10.4, carrier:

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Adenovirus 35 vector + modified vaccinia Ankara vector, phase IIa), and MVA85A (antigen: Ag85A, carrier: modified vaccinia Ankara, phase IIb) and represent pre-exposure vaccines that are administered to newborns and adolescents with the aim of preventing infection with TB (Andersen and Kaufmann 2014). The development of new TB subunit vaccines remains a challenge due to the lack of proper adjuvants to elicit potent Th1 responses. Adjuvant-based TB vaccines include H4/IC31 (preventive) (antigen: Ag85B and TB10.4, carrier: IC31, phase IIa), M72 (preventive and postexposure) (antigen: Rv1196 and Rv0125, carrier: AS01E (liposomes and MPL), phase IIa), ID93 (preventive, postexposure, and therapeutic) (antigen: Rv2608, Rv3619, Rv3620 and Rv1813, carrier: GLA-SE, phase I), and H1/H56/IC31 (preventive, postexposure, and therapeutic) (antigen: Ag85B, ESAT-6 and Rv2660c, carrier: IC31, phase IIa) and are administered before and during the latent and active phases of TB infection as a “prime” instead of BCG, or as a booster to a BCG “prime” (Andersen 2007; Andersen and Kaufmann 2014). This is because the prime/boost strategy of immunization is more effective for enhancing humoral and cellular immunity that repeated administration of the same vaccine (homologous boosting), which mostly increases the humoral immune response, but not the cellular immune response to target antigens. The prime/boost strategy of immunization entails priming the immune system against a target antigen and then boosting antigen-specific immune responses with a specific immunogen, which is often a recombinant viral vector that expresses the same vaccine antigen. Another important point is the excellent function of the delivery systems associated with subunit vaccines in terms of enhanced immunity, in vivo stability, conformational integrity, and persistent and prolonged stimulation of the immune system due to the controlled release of the antigen (Kim et al. 2014; Peek et al. 2008). Thus far in this review, we have focused on recent reports concerning TB vaccines in order to evaluate the potential of using cationic liposomes as delivery systems/adjuvants for TB subunit vaccines.

3 Liposomes Nanostructures are widely used as drug and vaccine delivery systems (Ahmaditabar et al. 2017; Fasihi-Ramandi et al. 2017). Liposomes are closed, self-assembled vesicular and lipid-based nanostructures that were first discovered by Bangham et al. in 1965 (Alving et al. 2016). These spherical vesicles consist of either a hydrated bilayer, or multilayered lipids, that are composed of phospholipids or amphiphilic non-phospholipids such as cationic lipids (Alving et al. 2016). Biocompatible, and biodegradable, non-toxic liposomes are well tolerated by the human body and have extensive applications in drug delivery, gene delivery, cell delivery, and diagnosis of disease, and they find widespread use in cosmetics and the fields of dermatology and immunology (Garg and Goyal 2014; Vartak and Sucheck 2016). However, their use as adjuvants and, especially, as a vehicle for the successful delivery of vaccines has increased in the last decade (Vartak and Sucheck 2016).

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In 1974 and 1976, Allison and Gregoriadis reported that liposomes are able to increase the immune response (Schwendener 2014). They have two simultaneous properties, which include (1) immunostimulant characteristics by their interaction with immune cell receptors such as TLRs, and (2) carrier characteristics due to the depot effect and the subsequent gradual release of vaccine antigens (Schwendener 2014). One of the most important features of liposomes as a vaccine delivery system is their structural versatility and plasticity in terms of size, charge, encapsulation efficiency, and also the location of the entrapped actives that can carry different types of antigens and adjuvants (e.g., hydrophilic compounds, proteins, nucleic acids, and carbohydrates), inside the liquid space, and lipophilic compounds into the lipid bilayer (Schwendener 2014). It has been demonstrated that the physiochemical characteristics of liposomal vaccine adjuvants/delivery systems such as size, charge, lipid composition, and the nature and location of antigens in the particle, all have an important role in cellular uptake, transport to regional lymph nodes, and induction of a Th1 and Th2 immune response (Schwendener 2014; Vartak and Sucheck 2016). Therefore, particles with a size range of 20–200 nm have efficient uptake and transport to lymph nodes. However, for larger particles with a size range of 500–1,000 nm in size, uptake and transport to the lymph nodes is needed so that they can interact with activated dendritic cells that have previously migrated to the lymph nodes to interact with T- and B-cells to initiate the adaptive immune response (Vartak and Sucheck 2016). Previous studies have shown that small and large liposomes were able to induce a Th2 and Th1 immune response, respectively (Badiee et al. 2012). Positively-charged lipids, as well as the composition of lipids themselves, have a significant impact on stability, transfection activity, and induction of strong immune responses. Enhanced interaction, membrane fusion, and improved uptake by dendritic cells occur with positively-charged lipids that comprise cationic liposomes because, compared to neutral and anionic liposomes, cationic liposomes have shown greater uptake by APCs, macrophages, and dendritic cells (Hu et al. 2014; Vartak and Sucheck 2016).

4 The Role of Cationic Liposomes as TB Adjuvants Based on their composition and intended use, liposomes can be divided into conventional, pH-sensitive, stealth, immuno, magnetic, heat-sensitive, and cationic liposomes (Garg and Goyal 2014). The structure of cationic liposomes is composed of neutral (e.g., helper lipids, such as cholesterol) and cationic (e.g., cationic head groups, polyamines, tertiary or quaternary ammonium compounds, and linker and hydrophobic tail) lipids (Xiong et al. 2011). The most important cationic lipids are DDA, dimethyldioctadecylammonium, DOTAP, 1, 2-dioleoyl-3trimethylammonium-propane, DC-Chol, 3B-[N-(N0 , N0 -dimethylaminoethane)carbamoyl] cholesterol, DOEPC, 2-dioleyl-sn-glycero-3-ethylphosphocoline, DOTIM, octadecenoyloxy(ethyl-2-heptadecenyl-3-hydroxye-thyl) imidazolinium, CCS, N-palmitoyl-D-erythrospingosyl-1-O-carbamoyl spermine, diC14-amidine,

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3-tetradecylamino-tert-butyl-N-tetradecylpropionamidine, DOTMA, and N(1-[2,3-dioleyloxy]propyl)-N,N,N-trimethylammonium (Christensen et al. 2009). Although a great number of liposomal adjuvants have been tested in various stages of preclinical or clinical trials, only two liposomal adjuvants (Adjuvant System 01 (AS01) and virosomes) are among the six approved adjuvants for use in human vaccines (Alving et al. 2016; Brito and O’Hagan 2014; Garçon and Van Mechelen 2011; Glück et al. 2004). Currently, the AS01 adjuvant, in combination with the M72 subunit vaccine of TB, which contains antigens Rv1196 and Rv0125, has advanced in phase II clinical trials, and its proposed use is during the latent phase of a TB infection as a booster for a BCG prime (Wang et al. 2013). The high efficacy of Mtb immunodominant antigens is required for adjuvants. Cationic liposomal adjuvants have shown that they are suitable immunostimulatory adjuvants to induce a strong Th1 immune response against a TB infection (Hu et al. 2014) (Figs. 2 and 3). In this review, we have noted that the most commonly employed cationic liposomal adjuvants utilized to elicit a robust immune response against selected TB antigens included DDA-based adjuvants and DOTAP-based adjuvants.

Fig. 2 Cationic liposome-mediated CTL immune response. Cationic liposomes are proposed to cause dendritic cells to mature via activation of CD80/86 that binds to CD26 on the surface of naïve CD4+ T cells. Cationic liposomes also shift naïve T cells to Th1 cells by up-regulating the expression and secretion of Th1-defining cytokines such as IL-12 via activation of PI3 kinase that leads to the enhanced activity of P38, which then up-regulates the expression of IL-12. In addition, cationic liposomes enhance the expression and secretion of the CC chemokine CCL2 that induces migration and maturation of naïve CD8+ cytotoxic T cells. CCL2 is known to be up-regulated via the ERK1/2 pathway, which is induced via cationic liposome-activated PI3K

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Fig. 3 Cellular delivery mechanism of cationic liposomes. Cationic liposomes can be internalized into the cell through endocytosis via an endosome (step 1). After endocytosis, the cationic lipid destabilizes the endosomal membrane, which leads to a flip-flop of anionic lipids such as phosphatidylserine (step 2) that are predominantly presented in the cytoplasmic face of the endosomal membrane. The anionic lipids diffuse laterally into the liposomal bilayer and form a charged neutralized ion-pair with the cationic lipid (step 3). This process displaces all containedantigens of the cationic liposome into the cytoplasm. Afterward, released antigens can be processed through proteasome degradation and, then, assembled by MHC I molecules in the endoplasmic reticulum and, finally, presented on the cell surface. Presented antigens can then be recognized by cytotoxic T-cells

5 DDA-Based Adjuvants In 1966, Gall was the first to discover that DDA, as a quaternary ammonium compound, has potent adjuvant effect (Christensen et al. 2007). In recent years, the use of DDA liposomes as promising TB vaccine adjuvants has been extensively evaluated. The most important features of DDA as a TB adjuvant are: (1) there is strong absorption of antigens, (2) there exists an antigen depot effect at the injection site, and (3) there is more efficient cellular uptake of the antigen (Christensen et al. 2007). As seen in Table 1, the DDA liposomal adjuvant has been used in combination with other non-immunostimulatory molecules, including MPL (monophosphoryl lipid A), TDM (trehalose dimycolate), TDB (trehalose 6, 60 -dibehenate), BCG, and Poly I:C to induce a strong immune response against

Ag85A-HspX

Mtb10.4-HspX

Mtb10.4-Ag85B ESAT6-Ag85B ESAT6-RpfE ESAT6-Mtb8.4 EAMM MH

BCG

BCG

Recombinant ESAT-6 and Ag85B–ESAT-6 Myc3504 (rBCG)

Booster NA

BCG

BCG

NA

Vaccines Prime Ag85B-ESAT-6

DDA-TDM poly(I:C) gelatin

DDA-TDM

DDA and MPL

DDA and MPL

DDA, TDB, MPL

Adjuvant DDA/MPL

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Status Preclinical study

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously Intranasal

Subcutaneously

Administration route Intramuscularly

Mtb H37Rv

Mtb H37Rv

Mtb H37Rv

Mtb H37Rv

Mtb Erdman

Challenge Mtb Erdman

Table 1 Characteristics of cationic liposomes as Mtb vaccine adjuvants in some studies

Mice

Mice

Mice Guinea pig Mice

Mice

Animal Monkey

Induced higher IFN-γ responses as compared to BCG Induced effective protection against progressive TB, especially in the latent phase Induced both humoral and cellular immune responses and able to promote BCG-primed immunity and protective efficacy against TB infection Some of the fusion proteins were able to effectively protect against M. tuberculosis (EAMM), improve BCG-primed protective efficacy against TB infection, and lower bacterial counts in the lungs and spleens (EAMM+MH)

Outcome Induced both humoral and cellular (CD4 and CD8) immune responses and reduction of bacterial load in lung and protection against TB infection Synergistically induced strong Th1 cell responses

Xin et al. (2013)

Niu et al. (2011)

Jeon et al. (2011)

HoltenAndersen et al. (2004) Badell et al. (2009)

Reference Langermans et al. (2005)

56 F. Khademi et al.

ESAT-6:HspX: mFcγ2a ESAT-6:HspX: His NA

BCG

Ad-H4

H4

BCG

Ag85B, ESAT6, Mtb10.4, Ag85B- ESAT6, Ag85BTB10.4 MVA/IL-15/ 5Mtb

BCG

BCG Ag85B, ESAT-6 and Ag85B-ESAT-6

BCG

BCG

H1, H4, H28 and H56 CFP-10:HspX: Fcγ2a CFP-10:HspX: His ESAT-6:Fcγ2a ESAT-6:His

BCG

CAF01

DDA/MPL

DDA and MPL

DDA and MPL

CAF01

CAF01

CAF01 DDA-MPL CAF01

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Preclinical study Preclinical study

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Mtb Erdman

Mtb Erdman

Mtb Erdman

Mtb Erdman and H37Rv

NA

NA

Mtb Erdman NA

Mice

Mice

Mice

Mice

Mice

Mice

Mice

Mice

Induced protective immunity in mouse model of pulmonary TB Induced both CD4 and CD8 T responses as well as increased the protective efficacy against Mtb challenge

Induced very strong response and long-term memory immunity to both ESAT-6, Ag85B and the fusion proteins Adjuvants had beneficial effect on the immunogenicity of some antigens

Induced strong Th1 responses Adjuvants were safe and induced strong Th1-mediated immune response Recombinant protein plus CAF01 adjuvant were induced high level of Th1 immune response more than protein alone Induced very strong Th1-mediated immune responses

(continued)

Elvang et al. (2009)

Kolibab et al. (2010)

Dietrich et al. (2005)

Olsen et al. (2001)

Soleimanpour et al. (2015)

Kebriaei et al. (2016)

Hoang et al. (2013) Mosavat et al. (2016)

Cationic Liposomes as Vaccine Adjuvants 57

DDA/MPL

CAF01

NA

CFP-25, CFP-20.5, CFP-32, Ag85A and Ag85B Ag85B-ESAT-6

BCG

CAF01

CAF01

CFP-10:Fcγ2a CFP-10:His ESAT-6:CFP10:Fcγ2a ESAT-6:CFP10:His NA

BCG

DDA-BCG PSN

Adjuvant DDA-BCG PSN

Ag85B AMH AMM AMH+ AMM

Booster Ag85B AMM

BCG

Vaccines Prime BCG

Table 1 (continued)

Preclinical study

Preclinical study

Preclinical study Preclinical study

Preclinical study

Status Preclinical study

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Subcutaneously

Administration route Subcutaneously

Mtb H37Rv

Mtb H37Rv

NA

NA

Mtb H37Rv

Challenge Mtb H37Rv

Mice

Mice

Mice

Mice

Mice

Animal Mice

Induced both strong humoral and cellular immune responses and elicited significant protective immunity against TB challenge

Induced both strong humoral and cellular immune responses

Outcome AMM in combination with adjuvant induced both strong humoral and cellular immune responses, enhanced BCG-primed immunity and protection against TB infection Induced high levels of humoral and cellular immune responses and increased clearance of Mtb in the lungs of TB-challenged mice Induced strong Th1mediated immune response Induced strong Th1mediated immune response

Agger et al. (2008)

Sable et al. (2005)

Baghani et al. (2017) Farsiani et al. (2016)

Li et al. (2011)

Reference Luo et al. (2009)

58 F. Khademi et al.

LT70

DDA Poly I:C

Preclinical study

Subcutaneously

Mtb H37Rv

Female C57BL/ 6 mice

Fusion protein in combination with adjuvants strongly induced both humoral and cellular immune responses Liu et al. (2016)

Myc3504 (rBCG) Ag85B-ESAT-6, EAMM ESAT6-Ag85B-MPT64190-198-Mtb8.4, MH Mtb10.4-HspX, CAF01 DDA-TDB, H1 Ag85B-ESAT-6, H4 Ag85BTB10.4, H28 Ag85B-TB10.4-Rv2660c, H56 Ag85B-ESAT-6/Rv2660c, MVA/IL-15/5Mtb a recombinant modified vaccinia Ankara overexpressing Ag85A, Ag85B, ESAT6, HSP60, Mtb39 and IL-15, Ad-H4 recombinant replication-deficient adenoviral 5 based vaccine, AMM Ag85B-Mpt64190–198-Mtb8.4, AMH Ag85B-Mpt64190–198-HspX, LT70 ESAT6-Ag85B-MPT64-(190–198)-Mtb8.4-Rv2626c, NA not available

BCG

Cationic Liposomes as Vaccine Adjuvants 59

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TB subunit vaccines. One reason for this is that the induced immune response against the subunit vaccine containing weak antigens, in combination with DDA adjuvant, is insufficient (Christensen et al. 2007). However, it has been shown that DDA in combination with the MPLA adjuvant led to induction of both a humoral and cellular (CD4 and CD8) immune response, reduction of the bacterial load in the lung, and protection against TB infection in various animal models when compared with DDA alone (Table 1). Induction of a strong T-cell response to TB subunit vaccines by DDA/MPL adjuvants is due to stimulation of APC cells through TLR-4 and induction of an antibody isotype switching to IgG2a, differentiation of Th cells to Th1, Th2, and Th17, and induction of a CD8 T-cell response (Christensen et al. 2007). Moreover, the adjuvant activity of DDA increased when used with TDM and induced both a humoral and cellular immune response, which was promoted by BCG-primed immunity and, therefore, protecting various animal models against a TB infection (Table 1). A combination of DDA and TDB known as “CAF01” showed a long-lasting depot effect at the site of injection, which induced both a strong humoral and cellular immune response, especially a Th1 response, as well as elicited significant protective immunity against a TB challenge (Table 1). CAF01 (DDA-TDB) is only one cationic liposome in combination with Hybrid 1, which contains Ag85A and ESAT-6 and is currently in phase II clinical trials (Wang et al. 2013). Use of this type of vaccine is as a prime or booster for immunotherapy against a TB infection (Wang et al. 2013). Furthermore, DDA, in combination with other adjuvants (Poly I: C), also triggered immunity against TB infections (Table 1). The present review suggests that simultaneous administration of cationic liposomes (DDA) with Poly I: C adjuvant (as a type I IFN-inducing TLR ligand) leads to a potent CD8 T-cell response to TB subunit vaccines. In the present review, we could not identify a study that used other cationic liposomal adjuvants to promote immune responses against TB subunit vaccines.

6 The Role of Cationic Liposomes as a TB Delivery System Using cationic liposomes as a carrier system to enhance the immune response against TB protein subunit vaccines is well documented due to three reasons: (1) inherent immunogenicity, (2) an antigen depot effect, and (3) optimal antigen delivery characteristic (Henriksen-Lacey et al. 2010a). Among cationic, anionic, and neutral liposomes used in the development of vaccine delivery systems, cationic liposomes interact more completely with the antigen. In addition, there is better retention of the vaccine at the site of injection, and thus, prolonged presentation of the antigen is achieved to induce Th1 and Th17 immune responses (Henriksen-Lacey et al. 2010b). Potent cell-mediated immune (CMI) responses, especially a Th1-type response, is a key factor with which to induce protection against a TB infection. Research has shown that replacement of cationic liposomes

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with anionic and neutral liposomes resulted in the production of a Th1 bias response (Hussain et al. 2014). The transfection mechanism by cationic liposomes is not fully understood. However, Felgner et al. demonstrated the ability of cationic liposomes to deliver immunogenic peptides into cells, and that this process occurs through simple fusion with the plasma membrane. However, others have reported that it occurs through endocytosis (Vangasseri et al. 2006; Xiong et al. 2011). Positively-charged cationic liposomes undergo electrostatic interactions with negatively-charged proteins, hydrophilic compounds, nucleic acids, carbohydrates, and mammalian cell membranes (Xiong et al. 2011). Cationic liposomes, after absorption by macrophages and dendritic cells, cause disruption of the endosomal membrane, which leads to release of antigens to the cytosol and subsequent induction of a potent cellular immune response (Vartak and Sucheck 2016).

7 DDA-Based TB Delivery System The synthetic amphiphilic lipid DDA has frequently been used to deliver different antigens of Mtb as subunit vaccines (Tables 1 and 2). The results of different studies presented in this review show that adsorption of antigen into DDA leads to enhanced uptake and presentation of the vaccine antigen to APCs, as compared with antigen alone (Table 2). Furthermore, simultaneous delivery of antigens and immunomodulators by a carrier leads to limited use of immunostimulatory components and reduces any toxic effects (Table 2). Various reports, along with the current review, have shown that separately administered delivery vehicles and single immunomodulators do not induce powerful immune responses and protection against a TB infection and, thus, are not an efficient TB vaccine (Li and Szoka 2007). As shown in Table 2, subunit vaccine delivery of TB by DDA liposomes, either alone, or in combination with immunomodulators, leads to induction of a Th1 response, maintains prolonged immunological memory, and a significant level of protection against TB infection. As it pertains to a DDA:TDB (CAF01) delivery vehicle, it should be noted that its effectiveness can be attributed to the synergistic effect of the components on the immune response, in which the cationic lipid component targets the TB antigen to APCs and the immunostimulatory component induces a proinflammatory response and the Th1 immune response (Li and Szoka 2007). It is also noteworthy that a DDA-based TB delivery system, with the same antigen, not only induces a strong IgG2a and IFN-γ response relative to other cationic liposomes (DOTAP and DC-Chol) and both neutral and anionic lipid liposomes, but also elicits long-term memory due to DDA’s depot effect and the slow or protracted release of the antigen (Table 2).

Booster NA

NA

NA

NA

NA

Vaccines Prime Ag85B-ESAT-6

Ag85B-ESAT-6

Ag85B-ESAT-6

Ag85B-ESAT-6

Hybrid56

DDA:TDB

DDA:TDB

DDA/BCG lipid (or MPL) DOTAP/BCG lipid DC-Chol/BCG lipid DDA:TDB, DOTAP:TDB, DC-Chol:TDB

Carrier DDA:MPL DDA:TDB

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Status Preclinical study

Intramuscularly

Intramuscularly

Intramuscularly

Subcutaneously

Administration route Subcutaneously

NA

NA

NA

Challenge Mtb Erdman and H37Rv Mtb Erdman

Table 2 Characteristics of cationic liposomes as Mtb vaccine delivery systems in some studies

Mice

Mice

Mice

Mice

Animal Guinea pig

Cationic liposomes showed longterm retention, slow release of antigen and potent Th1 immune response Prolonged antigen retention and antigen presentation as well as induce strong immune responses (Th1 and Th17) more than anionic and neutral liposomes. Also, induce low level of Th2 responses Produced higher IgG1, IgG2a, IL-2, and IFN-γ responses compared with antigen. Also, decrease in Th2 (IL-5 and IL-10) responses

Descriptions Induce significant level of protection against TB infection, as compared with antigen alone, close to BCG level Induce a powerful IgG2a and Th1 responses and maintain prolonged immunological memory superior to BCG

Hussain et al. (2014)

HenriksenLacey et al. (2010b)

HenriksenLacey et al. (2010a)

Rosenkrands et al. (2005)

Reference Olsen et al. (2004)

62 F. Khademi et al.

NA

NA

NA

NA

NA

Ag85B-ESAT-6

Ag85B MPT-64, MPT-83

DNA-hsp65

DNA-hsp65

DNA-hsp65

L-α-PC/ DOTAP/DOPE EPC/DOTAP/ DOPE and DOTAP/DOPE

EPC/DOPE/ DOTAP

PLGA+DDA

PLGA+DDA and PLGA +DDA+TDB

DSPC:Chol: DDA and DSPC:Chol: DDA:TDB

Preclinical study Preclinical study

Preclinical study

Preclinical study

Preclinical study

Preclinical study

Hybrid56 Ag85B-ESAT6-Rv2660c, NA not available

NA

Ag85B-ESAT-6

Intramuscularly

Intranasal

Subcutaneously Intramuscularly Intranasal

Intramuscularly

Subcutaneously

Subcutaneously

Mtb H37Rv NA

Mtb H37Rv

Mtb H37Rv

NA

Mtb Erdman

Mice

Mice

Mice

Mice

Mice

Mice

Addition of the cationic lipid to neutral liposomes leads to decrease in size, increase in entrapment efficiency and high levels of IFN-γ responses High antigen entrapment efficiency, prolonged release profile and induce both strong humoral and cellular immune responses Induce potent Th1 immune response due to the effect of DDA stimuli or sustained release DNA vaccine and a significant protection in mice after challenge with Mtb H37Rv Adjuvants/delivery systems/ DNA vaccine induced immune responses however do not prevent from TB infection Promising vaccine for Mtb treatment Induced IgG2a antibody production Rosada et al. (2012) de la Torre et al. (2009)

Rosada et al. (2008)

Cai et al. (2005)

Kirby et al. (2008)

McNeil et al. (2011)

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F. Khademi et al.

8 DOTAP-Based TB Delivery System DOTAP is a liposomal carrier/adjuvant with a strong positive charge. This quaternary ammonium compound has been used to induce protective immune responses against microbial infections in several studies (Christensen et al. 2007). These studies have demonstrated the therapeutic potential of DOTAP-based liposomes, as compared with antigen alone, in inducing both a humoral and cellular-mediated immune response, especially a Th1 response (Christensen et al. 2007). Compared with the DDA adjuvant, a few studies have used DOTAP-based delivery systems to enhance the immune response against TB subunit vaccines (Tables 1 and 2).

9 DC-Chol-Based TB Delivery System DC-Chol cationic liposome has been used as a carrier for the targeted delivery of subunit vaccines (DNA and protein antigens) (51). However, very few studies have evaluated the immunostimulatory capacity of the cationic lipid DC-Chol as a TB delivery system. Nevertheless, a DC-Chol-based TB subunit vaccine demonstrated long-term retention (antigen depot) at the site of injection, slow release of the antigen, and a potent Th1 immune response similar to the DDA-based TB delivery system (51).

10

Challenges of Cationic Liposomes

Despite the many potential applications for the use of cationic liposomes as extremely useful adjuvants/delivery systems against TB infection, their use is associated with the following limitations. First, they possess relatively weak adjuvant activity. Some studies have shown that many types of cationic liposomes, when used alone, exhibit relatively weak adjuvant activity. Therefore, to solve this problem, they are used in combination with other components (Alving et al. 2016). Another limitation of cationic liposomes (e.g., DDA as an adjuvant) is its instability in vivo (Christensen et al. 2007). Studies have shown that incorporation of immunostimulators (TDB (CAF01) or MPL or TMD) into DDA, in addition to the immunogenicity, also increases the stability of cationic liposomal adjuvants (Christensen et al. 2007). A third challenge to the use of cationic liposomes is their recognition and rapid elimination from the circulation by the reticuloendothelial system (RES) or the lung endothelial capillaries or proteins that function as opsonins and thereby make the adjuvant more susceptible to phagocytosis (Hashida et al. 2002; Li and Szoka 2007). Studies have shown that intravenous delivery of the cationic liposomes leads to interactions with serum proteins (e.g., serum albumin), an increase in particle size, and subsequent rapid elimination (Li and Szoka 2007).

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To overcome the rapid elimination in vivo, the surface of cationic liposomes can be covered with either a polymeric compound, be manufactured to have a size

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