Adipokines and their receptors: potential new targets in cardiovascular diseases.

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Medicinal Chemistry

Adipokines and their receptors: potential new targets in cardiovascular diseases

Adipose tissue is an ‘endocrine organ’ that influences diverse physiological and pathological processes via adipokines secretion. Strong evidences suggest that epicardial and perivascular adipose tissue can directly regulate heart and vessels’ structure and function. Indeed, in obesity there is a shift toward the secretion of adipokines that promote a pro-inflammatory status and contribute to obesity cardiomyopathy. The prospect of modulating adipokines and/or their receptors represents an attractive perspective to the treatment of cardiovascular diseases. In this paper, we described the most important actions of certain adipokines and their receptors that are capable of influencing cardiovascular physiology as well as their possible use as therapeutic targets.

Adipose tissue & the pathophysiology of obesity cardiomyopathy

Obesity is characterized by an increased deposition of both intra-abdominal and intrathoracic adipose tissue (AT) [1] . The Framingham Heart Study first showed that this condition is an important risk factor for the development of heart failure (HF) [2] . In fact, AT is nowadays considered as an important ‘endocrine organ’ with an intense metabolic activity. The molecules secreted by the AT are termed adipokines and participate, not only in energy metabolism, but also in a wide range of physiological and pathological processes [3,4] . The hemodynamic and metabolic alterations promoted by obesity predispose for significant cardiac morphological and functional changes. Over time these modifications lead to obesity cardiomyopathy, a particular type of HF characterized by cardiac hypertrophy and impaired contractility (Figure 1) [5,6] . Regarding intrathoracic AT, attention should be given not only to the intramyocardial fat content, but also to the AT surrounding the heart and vessels [7] . Indeed, the close proximity and the absence of muscle fascia between epicardial AT, perivascular fat, myocardium and blood vessels, provides conditions for a direct crosstalk between

10.4155/FMC.14.147 © 2015 Future Science Ltd

Nádia Gonçalves1, Inês Falcão-Pires1 & Adelino Ferreira Leite-Moreira*,1 1 Department of Physiology & Cardiothoracic Surgery, Cardiovascular R&D Unit, Faculty of Medicine, Universidade do Porto, Porto, Portugal *Author for correspondence: Tel.: +351 225 513 644 Fax: +351 225 513 646 [email protected]

them. Additionally to local effects, the AT also presents wider cardiac and systemic effects. The adipokines secreted are capable of crossing the coronary vessels’ wall acting through a ‘vasocrine signaling mechanism’ (Figure 2) [8] . Indeed, a dichotomous protective and detrimental role of the epicardial AT and perivascular fat has been described [9] . Besides modulating energy sources under physiological conditions, epicardial AT exerts protective effects on vascular and myocardial function through the secretion of vasodilators and inotropic adipokines. However, during fat expansion, an injurious action is triggered and an increase in lipotoxicity, as well as in prothrombotic and pro-inflammatory mediators is observed [7] . Several cardiovascular risk factors such as metabolic syndrome, hypertension, atherosclerosis, coronary artery disease (CAD) as well as left ventricle (LV) hypertrophy and diastolic dysfunction correlate with increased epicardial AT and obesity cardiomyopathy [10] . Although a solid association between overweight, obesity and the development of cardiovascular diseases (CVD) is well recognized and accepted, many studies revealed a better prognosis for HF patients who are overweight or obese [11] . The beneficial effect of AT expansion in end-stage HF has been named the

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Review Gonçalves, Falcão-Pires & Leite-Moreira

Key terms Obesity: Between 1980 and 2008, the prevalence of obesity worldwide virtually doubled. In the WHO European Region 30–70% of the adult population is overweight whereas 10–30% suffers from obesity. Among this population, approximately 23% of women and 20% of men were considered obese. (WHO, European Statistics 2013). Adipokines: Molecules secreted by the adipocytes and stromal fraction of the adipose tissue that mediate the endocrine actions of this ‘organ.’ Alterations promoted by obesity: During adipose tissue hypertrophy, there is an overexpression of detrimental adipokines and diminished secretion and/or resistance of the protective ones. Obesity cardiomyopathy: In obesity, adipokines derived from adipose tissue induce detrimental cardiovascular structural remodeling and impaired myocardial function. Epicardial adipose tissue: Epicardial adipose tissue is a cardiac fat depot surrounding the heart. Its thickness correlates with metabolic syndrome and coronary artery disease and might represent a tool for cardiometabolic risk prediction.

‘obesity paradox’ or ‘reverse epidemiology’ [12] and several hypotheses have been proposed to explain it. First, obese HF patients may have more metabolic reserves to deal with the catabolic status; second, their AT secretes adipokines that exert protective actions such as soluble TNF-α receptors; and finally, they can have decreased response to the renin-angiotensin-aldosterone system (RAAS) [4] . The evidence that several adipokine receptors are expressed in the myocardium and that epicardial and perivascular AT strongly influence the cardiovascular system, modulating heart and vessels structure and function, led to the hypothesis that adipokines and their receptors may represent attractive therapeutic targets in obesity cardiomyopathy. In this regard, the present paper reviews the physiological and pathological effects of some adipokines involved in CVD as well as the therapeutic options that these molecules and their receptors represent (Figure 3) . The apelin receptor (APLNR) The discovery of the apelinergic system was first reported by O’Dowd in 1993 when APJ (recently designated apelin receptor, APLNR) was identified [13] . However,

Adipose tissue Deleterious effects of obesity in the adipose tissue and cardiovascular system

• Adipocyte hypertrophy • Macrophage infiltration • Angiogenesis • Proinflammatory state

Macrophage

Vasculature • Pro-atherosclerotic environment • Endothelial dysfunction Adipocyte Vasculature

Adipokines Adiponectin

Downregulation

Apelin

Visfatin FABP S100 family

• ECs and VSMCs migration and proliferation Heart

Leptin Resistin

• Adhesion molecules expression

• Cardiomyocyte hypertrophy Upregulation

• Fibroblast proliferation • Fibrosis deposition • Mitochondrial dysfunction and apoptosis • Lipotoxicity and ROS overproduction • Ca2+ handling impairment

Figure 1. Effects of obesity in adipose tissue and cardiovascular system. During the development of obesity, there is a shift in secretion of adipokines with an upregulation of injurious mediators and a downregulation of the beneficial ones. These molecules alter the adipose tissue, myocardial and vessel structure and function, leading to obesity cardiomyopathy. EC: Endothelial cell; ROS: Reactive oxygen species; VSMC: Vascular smooth muscle cell. Figures were produced using Servier Medical Art.

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Adipokines & their receptors

only in 1998 Tatemoto et al. [14] was able to detect apelin (APLN), the APLNR endogenous ligand peptide. In humans, apelin has several biological isoforms (APLN-12, -13, -17, -36 and the pyroglutamylated apelin-13) exhibiting different affinities to the apelin receptor [15,16] . Interestingly, apelin is not the only stimulus for this receptor as myocardial stretch seems to activate its signaling pathway [17] . Moreover, apelin and angiotensin II (Ang II) type 1 (AT-1) receptors can heterodimerize.

Review

This leads to a modification in the signaling pathways and to the repression of AT-1 by the APLNR [18] . In humans, APLN and its receptor are ubiquitously expressed, with particular importance in central nervous system, heart, lungs and adipose tissue [19–23] . Because apelin is produced in adipocytes and regulated by body composition and insulin levels, it has been designated as an adipokine [24] . Apelin is stimulated by insulin levels, being able to regulate energy metabolism by improv-

Influence of the perivascular adipose tissue in obesity

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Figure 2. Influence of the perivascular adipose tissue in blood vessels. Fat depots contiguous to the vasculature influence its physiology in a ‘vasocrine way.’ The adipokines secreted during fat expansion participate in the genesis of atherosclerotic plaque as in the remodeling underneath hypertension development. EC: Endothelial cell; VSMC: Vascular smooth muscle cell. Figures were produced using Servier Medical Art.


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Review Gonçalves, Falcão-Pires & Leite-Moreira ing insulin sensitivity and by inhibiting AT lipolysis [25] . Indeed, increased plasma levels of APLN-12 in obese children were associated with elevated insulin levels and triglycerides content [26] . Besides presenting antiobesity and antidiabetic actions, apelin is also a potent vasoactive agent [6] .

Key term Perivascular adipose tissue: Adipose tissue surrounding blood vessels that modulate their function, structure and metabolism in a ‘vasocrine’ way. In the heart, this depot is preferably around the major trunks of the epicardial coronary arteries.

A Endothelial cell

Atherosclerosis

Arterial hypertension APLN

ADIPO

Resistin APLNR α γ

Leptin

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ADIPO

ObR

?

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S100 A8/A9

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NF-κB

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Adhesion molecules Atherosclerotic factors Angiogenesis mediators

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Vasodilation of VSMCs

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Arterial hypertension Ang II

B Vascular smooth muscle cell

Apoptosis inflammation

ADIPO

APLN Physical interaction

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Figure 3. Adipokine pathways and effects on (A) endothelial cells, (B) vascular smooth muscle cells and (C) cardiomyocytes. Inside the gray boxes are some of the pathologies that can be the target of adipokines and their receptors modulation. ADIPO: Adiponectin; AdipoR: Adiponectin receptor; Ang II: Angiotensin II; APLN: Apelin; APLNR: Apelin receptor; AT-1: Ang II receptor type 1; ObR: Leptin receptor; VSMC: Vascular smooth muscle cell. Figures were produced using Servier Medical Art.

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C Cardiomyocyte

Myocardial infarction

Obese Systolic dysfunction cardiomyopathy

S100A1

obR

APLNR

α

Hypertrophic cardiomyopathy

Leptin

FABP

APLN

Review

Transporter

β γ

Nucleus

PLC

Hypertrophy

Inflammation apoptosis

Ca+2 handling impairment

PKC

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NHE Na+

H-

P13K Ca

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ERK ?

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Mitochondria AdipoR Several proposed S100A1

Systolic dysfunction

ADIPO

Hypertrophic cardiomyopathy

Figure 3. Adipokine pathways and effects on (A) endothelial cells, (B) vascular smooth muscle cells and (C) cardiomyocytes (cont.). Inside the gray boxes are some of the pathologies that can be the target of adipokines and their receptors modulation. ADIPO: Adiponectin; AdipoR: Adiponectin receptor; Ang II: Angiotensin II; APLN: Apelin; APLNR: Apelin receptor; AT-1: Ang II receptor type 1; ObR: Leptin receptor; VSMC: Vascular smooth muscle cell. Figures were produced using Servier Medical Art.

In the cardiovascular system, its expression was detected in endothelial cells (ECs) of small intramyocardial vessels, coronary arteries and endocardial cells. Cardiomyocytes and vascular smooth muscle cells (VSMCs) also produce this adipokine, although to a minor extent [27,28] . Moreover, the apelinergic system has been involved in the regulation of cardiovascular function, vascular tone and embryonic development [29] , as well as cardiac and systemic volume adjustment [30] . Finally, it is similarly implicated in several CVD, namely, hypertension and HF [31] . Cardiovascular actions

One of the first actions reported for APLN in the cardiovascular system was a decrease in mean blood pressure after intravenous injection in Wistar Kyoto and spontaneously hypertensive rats [32] . Controversially, other investigations described an increase in mean


arterial blood pressure [33] . These opposite results may be explained by different experimental conditions or by recent evidences showing the importance of endothelium integrity for apelin’s regulation of vascular tone. Apparently, when the endothelial APLNR is activated, a vasodilator response in VSMCs is initiated via a PI3K/AKT/NO dependent mechanism (Figure 3A) . However, in the presence of endothelial dysfunction, apelin acts directly on the VSMCs receptor inducing vasoconstriction through myosin light chain phosphorylation by PKC and MLCK activation (Figure 3B) [33,34] . Another evidence of the role of the apelinergic system in the homeostasis of blood pressure is the fact that long-term exercise reduces the blood pressure of spontaneously hypertensive rats, while preventing downregulation of the system. In fact, some beneficial consequences of exercise are supposedly linked to the apelinergic system overexpression [35] .


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Review Gonçalves, Falcão-Pires & Leite-Moreira Several vasoactive functions of the APLNR are associated with the RAAS, having these two axis opposite actions in both physiological and pathological processes. The counter regulatory role was demonstrated by increased vasoconstriction in response to Ang II in apelin receptor-deficient mice [32] , as well as to apelinmediated vasodilatation of arterioles constricted with Ang II [18] . These effects were attributed to apelins’ ability to increase NO production in ECs (Figure 3A) as well as to decreased AT-1 activation due to a physical interaction between the two receptors (Figure 3B) [18] . Additionally, Barnes et al. performed a series of randomized placebo-controlled studies to verify the effect of the prolonged agonism of the APLNR and the effect of the concomitant activation of the RAAS. They demonstrated that cardiovascular apelin actions were not modified by simultaneous co-infusion of Ang II in controls or HF patients, supporting the hypothesis of apelin as a novel therapeutic option in hypertensive patients resistant to RAAS blockers [36] . This association was further supported by the discovery that ACE2 also cleaves some apelin isoforms [37] and that apelin increases ACE2 promoter activity and expression [38] . All these observations suggest that modulating APLN, its receptor and ACE2 can represent a potential approach to treat hypertension. However, caution should be taken while planning an experimental design aiming to increase apelin levels by blocking ACE2 since it would probably prevent the beneficial effects of Ang 1–9 and 1–7 [39] . Another important mediator of vascular tone and volume regulation is vasopressin. This peptide presents contrary actions to those of APLN, promoting vasoconstriction, water intake and renal reabsorption. Indeed, apelin synthetized in the brain directly inhibits the vasopressinergic neuron activity through the apelin receptor [40] . More recently, a study suggested that the increased volemia of patients under peritoneal dialysis triggers increased APLN plasma levels in order to maintain compensatory diuresis alongside with the inotropic and vasodilator effects [28] . One of the most captivating cardiovascular properties of the apelinergic system is its potent positive inotropic effect. The first studies conducted by Szokodi et al. in isolated perfused rat hearts demonstrated a dose-dependent powerful and efficacious positive inotropic response [41] . Later studies also in rodents showed that chronic APLN infusion resulted in increased contractile reserve and cardiac output as well as decreased LV preload and afterload [42] . The peculiarity of this inotropic agent is that the increased contractility is not due to a hypertrophic response, highlighting its potential use in the treatment of systolic dysfunction. Furthermore, it was

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suggested that this improved ventricular contraction may be a result of increased intracellular Ca 2+ transients through activation of PLC, PKC, and NHE and NCX in healthy and hypoxia-induced pulmonary hypertension (PH) rats (Figure 3C) [41,43] . Compared with several other inotropic molecules, apelin presents the particularity to enhance biventricular function without inducing hypertrophy in HF rat models induced by isoproterenol [44] or by monocrotaline [45] . Role in cardiac remodeling & heart failure

Currently, there is no consensus on the plasma level of APLN, being reported 0.12 to 3760 pg/ml in healthy human controls and 0.06 to 4111 pg/ml in HF patients [30,46 –,49] . These differences possibly result from different methodologies, many of them detecting several isoforms simultaneously [28] . However, clinical studies in HF patients demonstrated increased plasma levels of apelin in the early stages, whereas normal [46] to lower levels [47] were reported later in the disease. These results indicate that the increased apelin might act initially as a compensatory response, but with the onset of chronic HF, their levels fall progressively probably related to the endothelial dysfunction that characterizes this syndrome [30] . This relationship between circulating apelin and HF is so relevant that in 2005 the plasma levels of apelin were suggested as an HF marker [50] , although its use in clinical practice was never implemented. Apelin presence was reported in the coronary circulation of normal individuals while in HF patients it was also detected in cardiomyocytes [46] . Previous results from our group confirmed the elevated APLN plasma levels and a direct correlation with LV mass index as well as an inverse correlation between the circulating apelin and its myocardial expression. We observed decreased LV myocardial expression of the system but higher apelin plasma levels under hypertrophic conditions in both animals as in aortic stenosis patients, suggesting a possible compensatory mechanism [51] . The density of the apelin receptor shows the same pattern with an upregulation in the beginning of the disease, decreasing its expression in more advanced stages [52] . In an isoproterenol rodent model of severe HF, APLNR showed a diminished expression, nevertheless the binding capacity of the receptor was increased. A more efficient post-transcriptional processing, a decrease in breakdown of the existing receptor or even a change in recycling could explain the improved binding capacity [44] . In right ventricle (RV) HF, the myocardial expression of the apelinergic system was decreased whereas APLN plasma levels were elevated. When administered chronically in monocrotaline-induced PH rat model,



apelin prevented the myocardial downregulation of this system while avoiding the activation of several vasoconstrictor neurohumoral systems that are typically overstimulated in PH. All these features translate in a slower progression of PH and diastolic dysfunction with lower RV pressure overload and hypertrophy [45] . Although during the establishment of HF the apelinergic system is upregulated, the exogenous administration of apelin is able to increase contractility. These reports suggested an impairment of the system in which the endogenous production is not enough to saturate apelin receptor, further supporting the idea of its therapeutic potential in patients with impaired systolic function [29] . However, a recent report suggested caution in using APLNR activation to improve cardiac function and delay the structural changes. Studies in cells expressing APLNR under stretch condition and in the absence of apelin activity presented contractile dysfunction. These surprising results suggested an apelin-independent activation of APLNR under stretch conditions that results in impaired systolic function. Subsequent experiments demonstrated that this response is different from the one initiated by apelin and depending on β-arrestin activation. Finally, the authors proposed that APLNR was able to incorporate both apelin and stretch signals balancing the final cardiac effect [17] . Besides hypertrophy, apelin also impacts myocardial fibrosis. In a rat model of RV HF secondary to PH, chronic administration of APLN was able to normalize fibrosis levels [45] . Recent in vitro and in vivo studies performed in mice submitted to aortic banding have strengthened this relation. Apelin pretreatment was capable of inhibit the fibroblast activation promoted by TGF-β, as well as collagen production in normal mice. The apelin-dependent decrement in extracellular matrix (ECM) synthesis results from transcriptional repression of SphK1 expression preventing TNF-α increment via RhoA/ROCK pathway [53] . In ischemia/reperfusion rodent models, such as coronary artery ligation, isolated hearts and cardiomyocytes culture, APLN further revealed protective features at several levels. Administration of this adipokine after hypoxia diminished the infarct size, improved contractile function and decreased mitochondrial impairment, while attenuating endoplasmic reticulum (ER) oxidative stress [54–56] . The beneficial effects of the apelinergic system in cardiac structure and function were demonstrated in a high-fat diet induced obesity model [25] . After the establishment of obesity cardiomyopathy, apelin treatment reverted weight gain, metabolic impairment and ER stress. At cardiac level, apelin restored the cardiomyocytes size and improved cardiac diastolic function


Review

by re-establishing the levels of SERCA, decreasing PLB phosphorylation as well as increasing mitochondrial respiration efficiency. Additional studies showed that apelin exerted direct actions in cardiac structure and function and the effects observed were not due to body weight loss or improvement of the metabolic status, but a direct effect of this adipokine [25] . These results confirm the protective and beneficial role of APLN in obesityassociated cardiac complications besides hypertrophic cardiomyopathy and myocardial infarction. Adiponectin receptors (AdipoR) Adiponectin is the main adipokine produced by the AT, representing 0.01% of the total plasma proteins [57] . Adiponectin 30 KDa monomers can combine into several isoforms, namely, small trimer and hexamer fragments and a most abundant high-molecular weight form (HMW) [58] . Besides these oligomers, adiponectin can suffer proteolysis, resulting in a smaller globular domain fragment [59] . All of these adiponectin products present different signaling pathways and intracellular properties. In fact, Tsao et al. showed that oligomerization seemed to be important to activate a NF-κB pathway since only HMW and hexamer isoforms were able to trigger a response [60,61] . A later experiment by the same authors revealed that exclusively the trimer fragment instigates phosphorylation of AMPK. Furthermore, a study in mice demonstrated a significant gender difference. The authors reported higher female levels of HMV and that this isoform is negatively regulated by plasma insulin [62] . Adiponectin can bind to three receptors (AdipoR) belonging to two different families. The first type of receptors contain seven transmembrane domains. The AdipoR1 is expressed especially in skeletal muscle, and the AdipoR2, predominating in the liver [63] . Finally, the third receptor has a T-cadherin structure [64] . Human, rat and murine cardiomyocytes are capable of producing and secreting adiponectin as well as expressing the three receptors [65–67] . The most important actions of adiponectin are to promote fatty acid oxidation and glucose uptake as well as to decrease glucose-induced ROS synthesis [68] . Moreover, the downregulation of adiponectin and its receptors in obesity is related to insulin resistance and intramuscular deposition of lipids [69] . Considered a protective adipokine, adiponectin is associated with cardioprotection in addition to antiinflammatory, antioxidant, anti-atherogenic and antiapoptotic actions [70] . One of the most attractive effects of adiponectin is its ability to protect against CVD through the modulation of myocardial remodeling, dysfunction and inflammatory state [3,71] . Plasma levels of adiponectin present a negative correlation with body mass index (BMI) [72] . In fact,


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Review Gonçalves, Falcão-Pires & Leite-Moreira low plasma levels are associated with obesity, Type 2 diabetes mellitus (T2DM) [73] and increased risk to develop hypertension [70] . In CAD, decreased levels of adiponectin are indicative of symptomatic disease and increased inflammation [74] . These observations suggested its use as a therapeutic target in the abovementioned diseases. Anti-atherosclerotic & anti-inflammatory actions

The protective actions of adiponectin in the onset and progression of atherosclerosis are achieved by the regulation of several signaling pathways [75] . Adiponectin diminishes the activation of NF-κB and thus reduces the synthesis of endothelial adhesion molecules and macrophage transformation in foam cells [76] , while preventing the production of pro-inflammatory cytokines such as TNF-α in macrophages [77] . Actually, some of the anti-atherosclerotic properties of adiponectin are due to the reduced production of inflammatory molecules mediated by macrophages, monocytes and endothelial cells [78] . Decreased secretion of adiponectin was also observed in adipocytes cultured with inflammatory cytokines and in plasma of obese patients [79] . The results suggest that the high cytokine levels in obesity might participate in the hypoadiponectinemia and insulin resistance observed in this condition. In fact, larger epicardial AT is related to low adiponectin levels, increased secretion of several proatherosclerotic and pro-inflammatory mediators as well as with higher cardiovascular risk [10] . Activation of adiponectin receptors is able to prevent VSMCs migration and proliferation into atherosclerotic lesions [80–82] , an effect achieved by diminished expression of adhesion molecules like VCAM, E-seletin and ICAM-1 in ECs via inhibition of NF-κB activation (Figure 3A) [76] . Furthermore, in VSMCs adiponectin can directly bind to PGF receptor and inhibit ERK signal preventing proliferation of these cells (Figure 3B) [80] . Cardiac remodeling & hypertension

Adiponectin role as therapeutic agent can also be highlighted by its beneficial actions in cardiac remodeling. In a model of myocardial ischemia, adiponectin averted cardiac hypertrophy and interstitial fibrosis besides diminishing myocyte and capillary loss, thus preventing systolic dysfunction [83] . Likewise, in genetic and in surgical models of cardiac hypertrophy adiponectin attenuated cardiac growth [81] . In humans, lower levels of adiponectin correlated with a faster progression of left ventricular hypertrophy and diastolic dysfunction [84] . Fujioka et al. demonstrated that the antihypertrophic response of full and globular adiponectin was mediated by myocardial AdipoR1 and AdipoR2 by two distinct pathways. They described

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a decreased synthesis of hypertrophic proteins by the AMPK/PI3K/AKT pathway as well as AMP/ERK/ mTOR signaling (Figure 3C) [66] . AMPK signaling is associated to other attractive cardiac effect of adiponectin that can potentially be used to prevent the deleterious effects of myocardial infarction. A single administration post-hypoxia-reoxygenation inhibited apoptosis in cardiac myocytes (Figure 3C) and fibroblasts, reducing the infarct size. Clinically, this is a promising therapeutic approach in acute myocardial infarction. The reduction of apoptosis can be useful not only in atherosclerosis but additionally in the treatment of myocarditis as demonstrated by the reduced number of apoptotic and infiltrating cells in Lepob/ob mice after adiponectin administration [85] . Lower circulating adiponectin is also associated with the development of hypertension. A 5-year prospective study in normotensive subjects demonstrated that decreased serum adiponectin was linked to an increased risk of developing elevated blood pressure [70] . In hypertensive patients, hipoadiponectinemia was associated with the progression of arterial stiffness and epicardial adiponectin decreased expression inversely correlated with the extension of CAD [86,87] . Furthermore, in obese hypertensive mice with hypoadiponectinemia, the overexpression of adiponectin was able to decrease blood pressure and restoring the decresed expression of eNOS [88] . Salt-induced hypertensive adiponectin-deficient mice submitted to ischemia/ reperfusion exhibited decreased eNOS and augmented iNOS activity, which resulted in elevated apoptosis, ROS production and infarction size. Conversely, adiponectin administration reduced iNOS activity and decreased infarction size [89] . Moreover, it has been reported that perivascular and epicardial AT secrete adiponectin and other vasoactive mediators that act in ECs to promote a weaker response to vasoconstrictive drugs [7,10] . These results reinforce the hypothesis of the role of epicardial AT in the development and progression of cardiac and endothelial dysfunction. Several mechanisms such as RAAS and sympathetic nervous system increased activity, endothelial dysfunction and impairment of renal pressure natriuresis have been suggested to underlie the association between adiponectin and hypertension [58] . Actually, increasing adiponectin plasma levels is one of the pleiotropic effects of angiotensin receptor blockers, which further attenuates hypertension [68] . Leptin receptors (ObR) Leptin, encoded by the obese gene (ob), was the first adipokine discovered that led to the recognition of AT as an ‘endocrine organ.’ Its secretion is positively correlated with BMI and has a more significant



production in subcutaneous AT than in the visceral AT [90] . Energy levels [91] , circulating insulin [92] , hormones [93] and inflammatory cytokines [94] are involved in the modulation of this cytokine-like circulating hormone. Six isoforms of the leptin receptor (ObR) have been described (a to f), all belonging to the class I cytokine receptor family, being ObRb the longer receptor and suggested as the main responsible for the effects of leptin on energy metabolism [95] . An abundant expression of both leptin and ObR was reported in many organs of numerous species, including the human cardiovascular system [96] . This wide expression is related with the most known actions of leptin, for example, reduction of food intake, regulation of energy expenditure, fertility and bone metabolism. Also, this adipokine can act directly in the central nervous system increasing thermogenesis and metabolic rate, thus contributing to the body homeostasis [73] . Hyperleptinemia & leptin resistance

Initial data indicated leptin as an anti-obesity adipokine. Clinical studies demonstrated leptin beneficial and safety use in obese subjects being able to ameliorate glycemia control and plasma triglyceride values in patients with lipodystrophy [97] . Paradoxically, the plasma levels in obese patients are upregulated (31.3±24.1 ng/ml vs 7.5±9.3 ng/ml in normal weight subjects) [98] , the anorectic effect is absent and the exogenous administration is unable to revert obesity [99] . These observations led to the theory of leptin resistance, which states that reduced sensitivity to leptin decreases its signaling pathway, failing to induce satiety and leading to obesity. In fact, a reduced access of leptin to the hypothalamus, neuron intracellular signaling defect [100] , genetic variations of leptin or ObR, ER stress and increased inflammatory mediators are proposed as contributors for leptin resistance [68,100] . Possibly, increased AT in obese patients originates leptin overproduction in order to restore homeostasis. Elevated levels of leptin were also correlated with detrimental effects in cardiovascular function such as induction of inflammatory response and stimulation of VSMCs proliferation (Figure 3B), oxidative stress and platelet aggregation (Figure 3A) [96] . All of these are mechanisms involved in endothelial dysfunction and atherogenesis. Elevated circulating leptin was also detected in patients with ischemic heart disease as well as in patients with HF and were associated with an increased hypertrophic response and worse prognosis [101] . Inflammation

ObR signaling pathways have been involved in several mechanisms of the inflammatory response and leptin


Review

presents a structure similar to cytokines, being considered the link between energy homeostasis and the immune system [102] . In fact, immunodeficiency is a common feature in several models of obesity with impaired leptin signaling or in leptin deficient-mice. Furthermore, ObR activation induces overexpression of proliferative and profibrotic cytokines [103,104] . Rodents submitted to acute starvation presented decreased circulating leptin levels as well as depressed immune system. The exogenous administration of leptin to these animals was able to reverse this response [105] . Recently, the association between obesity, leptin levels and inflammation was also demonstrated in obese adolescents. In this population, elevated blood neutrophil with increased degranulation were reported, further supporting leptin association with the immune system [106] . Additionally, leptin is related with the recruitment of inflammatory cells to the endothelial wall and platelet aggregation [58] , contributing to vascular inflammation and atherosclerosis [107] . The fact that leptin resistant or ObR knockout mice are incapable of developing atherosclerosis demonstrates its important role in this disease [96] . Dual vasoactive & cardiac actions

The cardiovascular beneficial effects of ObR signaling pathway include decreased lipotoxicity in the mitochondria, delaying apoptosis and a NO-mediated vasorelaxation (Figure 3C) . These cardioprotective effects are particularly relevant as a possible therapeutic approach to myocardial infarction and atherosclerosis (Figure 1) [108] . However, elevated leptin values are linked to higher blood pressure [109] , an effect associated to increased sympathetic activity in obesity-induced hypertension [110] . The attenuated vasodilation was also related to Ca 2+ handling abnormalities in the PLC pathway of VSMCs from aortic rings of spontaneously hypertensive rats pretreated with Ang II (Figure 1B) [111] . A disturbed NO signaling in ECs and VSMCs promoted by ROS and increased proliferation of VSMCs further contribute to vessel constriction [112] . Actually, changes in cardiomyocytes Ca 2+ handling were associated with elevated leptin in mice [113] and rat [114] . These alterations were ascribed to decreased NCX levels [115] , activation of endothelin 1 receptor and NADPH oxidase pathway [113] , besides JANK2, MAPK and NOS signaling [114] . Additionally, Mandani et al. showed that ObR activation resulted in decreased contractility and cardiac output, in addition to inducing ECM detrimental remodeling [116] . Globally, leptin beneficial effects in cardiovascular physiology are few, limited to protect the myocardium from ischemic events and hypoxia stress. In fact, leptin is considered a detrimental adipokine since it can lead


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Review Gonçalves, Falcão-Pires & Leite-Moreira to main effects include hypertension, inflammation, oxidative stress, endothelial dysfunction, hypertrophy and proliferation of VSMCs [58] . The advantageous properties of leptin seem to be dependent on the type of CVD, the existence of obesity and the related increasing in plasma leptin as well as the duration of the hyperleptinemia, since it trigger leptin resistance. Current research is focusing on leptin resistance and the mechanisms needed to reverse it. The results are very promising, however much is still to be done, namely, on how to apply this therapeutic option safely and on the identification of the substances that can be regulated downstream ObR activation [107] . Undiscovered adipokines receptors Several adipokines capable of influencing cardiovascular pathophysiology have been identified. Although their actions have already been described, their specific receptors and signaling pathways are not fully characterized. Resistin and visfatin are among these mediators. Resistin receptor

Resistin (or ‘resistance to insulin’) is defined as the hormone linking obesity and diabetes. This is based on the fact that its administration in mice induced glucose intolerance and insulin resistance, an effect reverted with an antiresistin drug [117] . In humans, this adipokine is synthetized especially by monocytes and macrophages from the stromal fraction of the AT and its expression is stimulated by several factors such as insulin, glucose, epinephrine and inflammatory mediators [118] . In fact, the increased plasma resistin levels observed in obese and diabetic subjects were correlated with inflammatory effectors and not with plasma insulin or glucose levels [119] . Later reports demonstrated that resistin participates in the recruitment of immune cells and production of pro-inflammatory mediators, suggesting its involvement in the genesis and establishment of atherosclerosis disease [118,120,121] . Resistin is able to influence several mechanisms of this pathology such as formation of foam cells, proliferation and migration of ECs and VSMCs as well as increased secretion of adhesion molecules [122–124] . Also, endothelial dysfunction caused by NO pathway impairment, modulation of vasoactive agents and upregulation of prothrombotic and pro-angiogenic agents have been ascribed to resistin (Figure 3A) [125–127] . Other features of resistin include the ability to directly influence myocardial structure and function by increasing apoptosis and cardiomyocytes’ size, modify the ECM content (Figure 3C) as well as disturbing Ca 2+ handling [128] . Finally, elevated resistin levels are also associated with higher cardiovascular risk and poor prognosis [129] .

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All these resistin effects suggest its downregulation as a potential option in the management of atherosclerosis, diabetes and myocardial Ca 2+ -induced dysfunction. Visfatin receptor

In 2005, visfatin was named after its identification by Fukuhara et al. as an adipokine produced especially in visceral AT [130] . Besides being termed as visfatin, this adipokine had previously been discovered and named differently by two other research teams: in 1994 as pre-B-cell colony-enhancing factor (PBEF) and related with the growth of B lymphocytes [131] ; and in 2002 as nicotinamide phosphoribosyltransferase (NAmPRTase or Nampt), an enzyme involved in nicotinamide adenine dinucleotide (NAD) biosynthesis [132] . Visfatin circulating levels are not consensual: while some authors report increased values in obese [133,134] and in diabetic patients [135] , others describe a decline in plasma visfatin levels [136–138] . These contradictory results might be partially explained by differential circadian and gender expression or even different quantification methods [139] . One of the first and most promising actions attributed to visfatin was its ability to bind and activate the insulin receptor [140] . Initially, these results made visfatin an interesting target for metabolic disorders treatment; however, elevated levels of this adipokine were later related with a pro-inflammatory condition and endothelial dysfunction [141,142] . In fact, visfatin can modulate numerous immune pathways by behaving as a cytokine and by increasing the secretion of monocyte adhesion mediators, contributing to atherosclerosis pathophysiology and plaque lesion instability [68] . Another visfatin effect involved in atherosclerosis is angiogenesis, promoted by migration and proliferation of ECs and VSMCs (Figure 3A & B) [143–45] . All these results lead to the association of visfatin to neovascularization in atherosclerotic plaques and in adipose tissue, creating the possibility of visfatin modulation in obesity. Recent data using genetically modified mice demonstrated an additional detrimental role for this adipokine in cardiovascular function. The authors reported that visfatin overexpression induced cardiac hypertrophy, whereas visfatin knockout mice were unable to respond to hypertrophic mediators (Figure 3C) [146] . Additionally, visfatin is also responsible for the increased cardiac fibroblast proliferation and collagen synthesis indicating its importance in myocardial remodeling [147] . Notwithstanding these deleterious effects, in 2008 Lim et al. reported that a single bolus injection of visfatin in mice submitted to myocardial ischemia/reperfusion diminished the infarct size by 30–50% and decreased apoptosis and oxidative stress



of isolated cardiomyocytes submitted to the same treatment [148] . In fact, the current knowledge suggests visfatin as a promising treatment in acute myocardial ischemia/reperfusion injury, especially in diabetic patients due to its effects in lowering glycemia [136] . The different cardiovascular effects of visfatin reported appear to be related to the duration of the treatment and the type of cell. While an acute administration of visfatin in ischemic conditions develops antiapoptotic actions in cardiomyocytes, a chronic treatment induces endothelial dysfunction, angiogenesis and atherosclerosis. FABPs receptors FABPs are a family of transporters for hydrophobic ligands such as fatty acid and other lipophilic substances, representing 1.8–8.1% of total cytosolic protein [149] . One of its members, FABP4 is abundantly secreted by adipocytes and macrophages from AT and cardiac ECs. Recently, a positive correlation between FABP4 mRNA levels and adipocyte size was demonstrated in epicardial AT from obese patients [150] . Moreover, FABP4-deficient mice are protected from insulin resistance, inflammation, atherosclerosis and metabolic syndrome [151,152] . Furuhashi et al. [153] demonstrated that downregulation of FABP4 and its receptor improved metabolism and inflammation in atherosclerotic disease and obesity. FABP4 inhibition in ApoE-/- mouse reduced atherosclerotic lesion area, foam cell formation, cholesterol ester accumulation and diminished secretion of inflammatory molecules [153] . In Lepob/ob mice, a 6 weeks inhibition of FABP4 enhanced insulin sensitivity, glucose metabolism and increased adiponectin levels without modifying body weight and fat depots content. The effect in insulin sensitivity was similarly observed in a diet-induced obesity model, demonstrating that inhibition of FABPs is effective in genetic and diet-induced obesity [153] . Furthermore, human genetic studies in polymorphism that reduces FABP4 activity describes decreased triglyceride levels, lower risk for CVD and T2DM [154] . These data additionally support the experimental studies showing that modulation of FABPs might be used to treat diabetes and CVD. Nevertheless, caution should be given to the fact that FABP4 acts as a cardiodepressor in obese patients by decreasing contractility and Ca 2+ transient in isolated rat cardiomyocytes (Figure 3C) [155] . S100 protein family receptors Until now, 24 proteins from the S100 family were identified, exerting intracellular and/or extracellular regulatory functions. A widespread expression of these


Review

proteins has been reported and several receptors proposed as mediators of their responses [156] . Actually, the S100 family is essential for many processes such as cell growth and differentiation, stress response, inflammation and was also considered a tumor marker. Several members of S100A and S100B proteins are expressed in AT and in heart and are involved in cardiovascular physiology and pathophysiology. For instance, in ischemic conditions, cardiomyocytes express S100B, which is able to reduce hypertrophy and preserve myocardial function [157] . S100A1 represents the most abundant S100 isoform in myocardium and skeletal muscle [158] . Pharmacological and surgical models of hypertension revealed a reduction of its expression associated with an impaired handling of the Ca 2+ by the sarcoplasmic reticulum through the inhibition of the cardiac ryanodine receptor [159] and compromised contractile performance (Figure 3C) [160] . S100A1 is also able to interact with titin improving compliance [158] as well as prolonging action potentials and amplifying the induced Ca 2+ transients by increasing calveolin-1 channel current [161] . Myocardial gene therapy studies demonstrated the effects of S100A1 as a positive inotrope and antihypertrophic adipokine (Figure 3C) [162,163] . It was suggested as a potential mediator of the progressive cardiac deterioration of HF patients due to its declined expression and normalization of S100A1 by gene therapy can be used to slow progression toward HF and improved survival in ischemic patients. S100A4 knockout mice submitted to transverse aortic constriction presented the same degree of hypertrophy observed in the controls but reduced proliferation of fibroblasts, interstitial fibrosis and profibrotic cytokines. These observations suggested that diminishing cardiac S100A4 would attenuate cardiac fibrosis in hypertrophic HF [164] . S100A9 is expressed in visceral and epicardial AT and is associated with obesity, inflammatory response and atherosclerotic plaque formation. It mediates processes such as the increase in ROS and cytokine production and also macrophage migration and adhesion [150] . In fact, neutralizing S100A9 with antibodies in an Ang II-induced hypertension model reverted the inflammatory response by decreasing cytokine expression and inflammatory cell infiltration. Furthermore, cardiac remodeling was reduced as demonstrated by diminished cardiomyocytes’ size and decreased perivascular and interstitial fibrosis [165] . Additionally, the dimer S100A8/A9 can represent a marker of adverse cardiovascular events. Different studies demonstrated that increased plasma levels can predict all-cause mortality and were correlated with elevated risk of a recurrent cardiovascular


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Review Gonçalves, Falcão-Pires & Leite-Moreira event [156] . Exogenous administration of S100A8/A9 resulted in increased secretion of pro-inflammatory cytokines and adhesion molecules besides promoting

apoptosis of ECs, suggesting that its inhibition might represent a therapeutic option for atherosclerosis (Figure 3A) [166] .

Executive summary Adipose tissue & the pathophysiology of obesity cardiomyopathy • Adipose tissue is an ‘endocrine organ’ that secretes adipokines which mediate pathological processes, namely obesity cardiomyopathy. • Epicardial and perivascular adipose tissue can directly influence the myocardium in a ‘vasocrine way’, playing both a protective and detrimental role. • Adipokines receptors may represent important therapeutic targets to treat obesity cardiomyopathy.

Apelin receptor • The apelin receptor is expressed in adipose tissue, heart and vessels, being activated by several apelin isoforms as well as by stretch conditions. • The cardiovascular properties of this adipokine include a potent vasodilator effect and a reducuction in preload and afterload. • The biventricular increased contractility evoked by the exogenous administration of apelin without inducing hypertrophy makes this system a potential target in HF. • Apelin plasma levels are increased in the early stages of HF as a compensatory mechanism, but decrease during the progression of the disease.

Adiponectin receptors • Adiponectin is the main adipokine produced by the adipose tissue, promoting fatty acid oxidation, glucose uptake and lower glucose-induced ROS synthesis. Furthermore, it has anti-inflammatory, anti-atherogenic and anti-apoptotic actions. • In obesity, downregulation of adiponectin and its receptors is related with insulin resistance, Type 2 diabetes mellitus and intramuscular deposition of lipids as well as increased risk of developing arterial hypertension and symptomatic coronary artery disease. • Adiponectin’s ability to prevent cardiac hypertrophy, interstitial fibrosis and reduce the infarct size makes it an interesting therapeutic target to prevent systolic and diastolic dysfunction.

Leptin receptors • Leptin was the first adipokine to be characterized and this anti-obesity hormone regulates food intake and energy expenditure. • In obesity, leptin plasma values are upregulated but the anorectic effect is absent due to leptin resistance. • In the cardiovascular system, elevated levels of leptin are correlated with endothelial dysfunction, atherosclerosis and adverse cardiac remodeling. • Modulating leptin resistance is now under investigation to improve cardiac function, particularly in obese subjects, but this topic remains controversial.

Resistin receptor • Resistin is the link between obesity and diabetes, inducing insulin resistance and glucose intolerance and elevated resistin levels are correlated with endothelial dysfunction, inflammation and atherosclerosis. • Apoptosis, cardiomyocyte hypertrophy and fibroblast activation are also promoted by this adipokine. • The association of increased resistin levels and higher cardiovascular risk and poor prognosis suggests that resistin downregulation is a potential therapeutic strategy for atherosclerosis and diabetes.

Visfatin receptor • Visfatin binds to the insulin receptor imitating its hypoglycemic actions. • In the heart this adipokine promotes angiogenesis, hypertrophy and collagen synthesis. • A single visfatin administration after myocardial ischemia/reperfusion diminished the infarct size by 30–50% making this adipokine an attractive therapeutic strategy for ischemic heart disease.

FABPs receptor • FABP4 is widely expressed by the adipose tissue and the heart, being associated with insulin resistance, metabolic syndrome, inflammation and atherosclerosis. • Modulating FABP in diabetes and CVD appears to be beneficial by improving energy metabolism, inflammation and myocardial contractility.

S100 protein family receptors • The most expressed cardiac isoform is S100A, a positive inotrope and antihypertrophic adipokine, capable of improving Ca2+ impairement. Its normalization by gene therapy might slow HF progression and increase ischemic patients’ survival. • The cardiac fibrotic response in hypertrophic hearts of subjects suffering from HF can be attenuated by decreasing S100A4 levels. • S100A9 is associated with overexpression of pro-inflammatory cytokines and infiltration of inflammatory cells, besides the reduction of fibrosis and cardiomyocytes’ hypertrophy. • The dimer S100A8/A9 is a potential marker of cardiovascular events because its increased plasma levels predicted all-cause mortality and were correlated with higher risk of a recurrent cardiovascular event.

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Conclusion & future perspective Nowadays, the increasing consumption of hypercaloric diets alongside a sedentary lifestyle rises the prevalence of overweight and obesity. These conditions are associated with the impairment of AT physiology, which overexpresses injurious adipokines and reduces the production, or develop resistance, to the beneficial ones. The metabolic and hemodynamic alterations triggered by these molecules culminate in cardiovascular dysfunction and obesity cardiomyopathy as illustrated in Figures 1 & 2. The increased knowledge on adipokines, their receptors as well as their signaling pathways raise the attractive hypothesis of their use as potential therapeutic target in CVD. Some adipokines initiate protective cardiovascular actions as seen by apelin’s biventricular positive inotropism without evoking hypertrophy; adiponectin’s anti-inflammatory, antidiabetic and anti-atherogenic actions; or S100A1 role in improving myocardial contractility and compliance. Leptin and visfatin dual effects are dependent on the duration of their increased plasma levels, the type of cell affected and the cause underlying the CVD. Targeting leptin receptor binding capacity and the access of leptin to its effector seems to be the path to use it as a therapeutic tool in obesity cardiomyopathy and atherosclerosis, whereas acute visfatin administration might be suitable in myocardial ischemia-reperfusion injury. Finally, obesity is associated with an inflammatory and proliferative state mediated by adipokines

that participate in the migration of macrophages and overexpression of cytokines and adhesion molecules. Resistin, FABPs and the S100 family are among these mediators and therefore their inhibition has been suggested as potentially beneficial, particularly in atherosclerotic disease. Despite these promising therapeutic targets, many adipokine receptors and signaling pathways are still to be discovered and clinical studies urge to unravel the potential of these molecules in the context of CVD.

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Acknowledgement We are very thankful to AF Silva, DM Gonçalves and PP Silva for their support in writing this article.

Financial & competing interests disclosure This work was supported by the Portuguese Foundation for Science and Technology Grants PEst-C/SAU/UI0051/2014, PTDC/BIM-MEC/0998/2012 and EXCL/BIM-MEC/0055/2012 through the Cardiovascular R&D Unit, by European Commission Grant FP7-Health-2010, MEDIA-261409 and by the Universidade do Porto/Santander Totta (Projectos pluridisciplinares IJUP 2011). N Gonçalves is supported by a grant from the Portuguese Foundation for Science and Technology (SFRH/BD/66628/2009). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized inthe production of this manuscript.

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Potential novel biomarkers of cardiovascular dysfunction and disease: cardiotrophin-1, adipokines and galectin-3.

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Implication of pattern-recognition receptors in cardiovascular diseases.

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Sigma receptors as potential therapeutic targets for neuroprotection.

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