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Cell Signaling Mechanisms Underlying the Cardiac Actions of Adipokines |
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hypertrophy.16 Leptin has also been shown to induce hyperplasia in the immortalized atrial HL-1 cell line via an ERK-dependent pathway.19 The results from studies using the HL-1 cell line are di cult to compare to primary culture of ventricular myocytes since the two models would likely respond to stimuli di erently in view of the fact that the primary response of HL-1 cells is hyperplasia, not hypertrophy. Recent evidence suggests that p38 activation (as well as activation of AMPK) mediates the anti-apoptotic e ect of leptin in cultured myocytes,42 although it should be added that STAT-3 activity has also been implicated in this phenomenon.43 Moreover, leptin-induced cardiac fatty acid oxidation has recently been demonstrated to occur by a multiplicity of cell signaling transducers including STAT-3, NO and p38 MAPK activation.44
4.6.3Pivotal Role for the RhoA/ROCK System in Mediating the Hypertrophic E ects of Leptin
Over the past number of years it has become apparent that the Rho/ROCK pathway, a downstream target protein of small GTP-binding protein Rho important for regulation of cell morphology, is likely also an important contributor to hypertrophy, although the mechanism leading to activation of Rho GTPases and subsequently to cardiac hypertrophy has not been well characterized.45,46 RhoA activates several protein kinases, including Rho kinases (ROCK). This leads to the activation of LIM kinase-2 (LIMK2) resulting in phosphorylation (inactivation) of the actin binding protein cofilin, an important factor in the regulation of actin dynamics, which in turn leads to depletion of globular actin (G-actin) pool and enhanced actin polymerization (F-actin). Work from our laboratory has recently shown that leptin is a potent activator of the RhoA/ROCK pathway leading to a decrease in the G/F actin ratio.47 The precise mechanism of how activation of this pathway leads to cardiac hypertrophy is not known with certainty. Interestingly, however, activation of RhoA/ROCK by leptin results in the selective translocation of p38, but not other MAPK isoforms, to the nucleus,48 a finding in agreement with our initial observation that leptininduced hypertrophy can be blocked by p38, but not by ERK inhibition.16 Intact caveolae are also critical for both the activation of the RhoA pathway and the resultant p38 translocation and hypertrophy.48 The role of caveolae in mediating the hypertrophic e ects of leptin was supported by various lines of evidence.48 Firstly, leptin significantly increased the number of caveolae as well as caveolin-3 protein expression in myocytes. Secondly, OBR were found to be colocalized with caveolae. Lastly, disruption of caveolae with the cholesterol-depleting agent methyl-beta-cyclodextrin was found to prevent leptin-induced hypertrophy, which was reversed by exogenous cholesterol repletion.
4.7 Adiponectin
Adiponectin is a 30-kDa protein secreted by adipose tissue that plays a critical role in di erentiation of adipocytes. The peptide belongs to the complement 1 family and can exist as a monomer or high-molecular-weight multimers.49
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Adiponectin can function as a full-length protein of 245 amino acids or a smaller globular fragment of 137 amino acids. The plasma adiponectin concentration in humans may range from 3 to 30 mg per ml and accounts for 0.01% of total plasma protein.50 Adiponectin expression and subsequent release from adipocytes is stimulated by activation of peroxisome proliferators-activated receptor (PPAR)-g, a key transcriptional factor involved in adipocyte di erentiation.51
Two adiponectin receptors, termed as AdipoR1 (adiponectin receptor 1) having 375 amino acids and AdipoR2 (adiponectin receptor 2) with 311 amino acids, have been identified.52 Structural analysis revealed that these receptors are integral membrane proteins containing conserved seven-transmembrane domains with internal N-terminus and external C-terminus.52 Scatchard plot analysis demonstrated that AdipoR1 binds to globular adiponectin whereas AdipoR2 binds to full-length adiponectin.52 AdipoR1 was shown to be expressed ubiquitously, while AdipoR2 expression is more restricted. In the heart, AdipoR1 is expressed in substantially greater abundance compared to AdipoR2.52
4.7.1Adiponectin and Cardiovascular Disease
Adiponectin is the most abundant adipokine secreted by adipose tissue and has been suggested to be involved in various cardiovascular diseases.53 Adiponectin levels are significantly reduced in obese subjects54 and patients with type 2 diabetes.55 The direct role of adiponectin in pathogenesis of cardiac disease still needs to be elucidated; however, it has been observed that increased plasma adiponectin levels are associated with a lower risk of myocardial infarction and coronary artery disease in men.56,57 Adiponectin levels were shown to be reduced significantly in patients with coronary artery disease58,59 as well as in patients with heart failure.60 In addition an inverse correlation was reported between adiponectin levels and other cardiovascular risk factors such as hyperlipidemia,50 hypertension61 and C-reactive protein levels.62 Adiponectin levels may also be a predictor of mortality in patients with chronic heart failure63 and coronary artery disease.64 A recent study showed a particularly strong relationship between elevated plasma adiponectin levels and mortality in patients with heart failure but an association was also present in patients without cardiovascular disease.65 However, an association between plasma adiponectin levels and cardiovascular morbidity or mortality is not uniform as recent studies were unable to demonstrate any relationship between plasma adiponectin levels and the severity of coronary artery disease.66–69 Such discrepant findings clearly support further research into the clinical relevance of adiponectin in cardiovascular disease. However, from a general perspective adiponectin exerts e ects opposite to those manifested in response to leptin and as such exerts primarily beneficial e ects in mitigating cardiac pathology.
4.7.2Adiponectin and Experimental Cardiac Hypertrophy
Adiponectin knockout (ADN-KO) mice subjected to pressure overload by transverse aortic constriction (TAC) demonstrate elevated concentric
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hypertrophy evidenced by increased left ventricular wall thickness as well as increased mortality after 7 days compared to wild-type animals. The adenoviral transfection of adiponectin (Ad-ADN) to ADN-KO mice 3 days prior to subjecting them to TAC attenuated the development of cardiac hypertrophy. In obese db/db mice, which lack the functional leptin receptor Ad-ADN, treatment abolished the TAC-induced increase in interventricular septum and left ventricular posterior wall thickness. In the presence of Ad-ADN, angiotensin II-induced cardiac hypertrophy was attenuated in both ADN-KO and wildtype mice.69 These findings suggest that adiponectin over-expression can reverse the cardiac dysfunction induced by various pathological factors. For example, a-adrenergic receptor stimulation by norepinephrine increased cell surface area and protein synthesis in cardiomyocytes, which was attenuated in the presence of adiponectin.69 Thus, adiponectin appears to be an endogenous anti-remodeling agent that may be beneficial in limiting heart failure.70
4.7.3Cell Signaling Mechanisms Underlying Cardioprotective and Antihypertrophic E ects of Adiponectin
Adiponectin induces e ects most likely via a multiplicity of cell-signaling mechanisms subsequent to adiponectin receptor (AdipoR1/AdipoR2) activation. For example, ERK1/2 MAPK activation was increased in ADN-KO mice subjected to TAC compared to wild-type. ERK1/2 activation induced by a-adrenergic agonist in cardiomyocytes was attenuated in presence of adiponectin or MEK inhibitor U0126.69 Taken together, these studies suggest that the protective e ect of adiponectin is partly mediated through inhibition of ERK1/2 MAPK.
AMPK modulation may also mediate some of the actions of adiponectin. In ADN-KO hearts AMPK phosphorylation at Thr 172 on a-subunit was suppressed compared to wild-type hearts.69 Moreover, activation of AMPK has been proposed as a mechanism for the beneficial e ects of adiponectin.69 ADNKO mice exhibit enhanced and accelerated myocardial remodeling following pressure overload, which is associated with reduced AMPK levels.71,72 Hearts from ADN-KO mice also developed larger infarct area compared to wild-type after subjecting them to ischemia/reperfusion (IR). In the presence of exogenous adiponectin, both ADN-KO and wild-type hearts had reduced infarct size after IR, an e ect associated with AMPK activation and suppression of TNFa production in myocardium.73 A role for AMPK has also been demonstrated in a study implicating adiponectin as the underlying factor in mediating cardioprotection in mice subjected to a calorie-restricted diet.74
Adiponectin has also been shown to attenuate the increased gp91 protein in cardiac tissue subjected to IR and thus reduced oxidative stress-induced tissue injury.75 Studies on the regulation of NO production from eNOS and iNOS by adiponectin demonstrated that in the hearts of ADN-KO mice subjected to IR eNOS phosphorylation is decreased and iNOS activity is increased compared to wild-type.75 This may suggest that under physiological conditions adiponectin
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increases the NO production from eNOS, which might contribute to its protective e ects, whereas during cardiac pathology adiponectin inhibits iNOS activation and thus reduces the NO overproduction, which can contribute to increased cardiac injury.
Another potential mechanism underlying the cardioprotective e ect of adiponectin may involve a stimulation of prostaglandin (PG) synthesis via the inducible cyclooxygenase-2 (COX-2) dependent pathway. In this regard, it was shown that adiponectin stimulates PGE2 synthesis and increases COX-2 expression in neonatal rat ventricular myocytes whereas a COX-2 inhibitor abrogated the infarct size sparing e ect of adiponectin in mice subjected to 30 minutes coronary artery occlusion followed by 48 hours of reperfusion.73 While the mechanism underlying the ability of adiponectin to upregulate COX-2 is not fully understood recent evidence suggests that this occurs subsequent to sphingosine kinase-1/sphingosine-1-phosphate receptor-dependent pathway.76
A recent study has also implicated PPARg activation as mediating the anti-hypertrophic e ects of adiponectin in a model of cardiac hypertrophy and remodeling produced by a high-fat diet,77 although a PPARa-dependent e ect has also been implicated at least with respect to angiotensin-2 induced cardiac fibrosis.78 Lastly, it has recently been reported that the anti-hypertrophic e ect of adiponectin in cardiomyocytes was associated with reduced heparin-binding epidermal growth factor (EGF) signaling, which included the downregulation of the EGF receptor.79
4.8 Resistin
A relatively new adipokine, resistin (for ‘‘resistance to insulin’’), was first identified in 2001 as a gene target of the insulin-sensitizing drugs thiazolidinediones (TDZs). Resistin is an adipose-derived secreted factor, produced almost exclusively in white adipose tissue. Resistin is a 12-kDa protein that circulates as either a trimer (monomeric form of the peptide hormone) or a hexamer (dimeric form of resistin). However, controversy remains as to which form, monomeric or dimeric, is responsible for the physiologic properties of the peptide.1 The monomeric form was shown to impair hepatic insulin action more potently than the dimerized form.80 In contrast, the dimerized form of resistin was shown to be more e ective in antagonizing insulin-stimulated glucose uptake in adult murine cardiomyocytes.81 Interestingly, the notion of di erential regulation of hormone signaling based on oligerimization state is shared by another adipokine, adiponectin.82,83 Resistin levels are elevated in patients with heart failure and may represent independent risk factors for heart failure development.84,85 Indeed, a recent study reported that resistin is expressed in the cardiac cell86 and its expression is increased by mechanical stretch, which occurs via a TNFa-dependent pathway involving MAPK and NF-kB activation.87 Resistin is a prohypertrophic factor acting via MAPK activation as well as increased phosphorylation of the insulin receptor
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substrate-1 (IRS-1).86 Thus, the contribution of resistin to the etiology of heart disease in general and heart failure in particular and the underlying mechanistic bases for these e ects is important to clarify particularly as targeting this cytokine may represent a possible useful therapeutic strategy.
4.8.1Cardiac Actions of Resistin
Emerging evidence suggests that cardiovascular disease is accompanied by changes in resistin levels. For example, in women, plasma resistin levels are elevated in patients with coronary heart disease.88 What role resistin plays in the disease process is not known, although in patients with atherothrombotic strokes, plasma resistin levels are associated with elevated risk of 5-year mortality.89 Serum resistin concentrations have also been shown to be elevated in patients with heart failure with levels positively related to the severity of heart failure according to New York Heart Association functional classification.90 Although these studies do not indicate cause-and-e ect relationships, nonetheless increasing plasma resistin concentrations appear to be a predictor of poor prognosis in patients with cardiovascular disease.
4.8.1.1Experimental Studies on the Cardiac Actions of Resistin
Although resistin cell receptors have yet to be identified, direct action of resistin in the heart and specifically on cardiomyocytes has been described. Mouse adult cardiomyocytes treated with resistin show a reduction in insulin-stimulated glucose uptake.81 Furthermore, in contrast to liver, cardiomyocyte resistin signaling requires oligomerization of the ligand prior to receptor binding.81 The precise mechanisms by which resistin exerts its e ects on glucose transport is not completely understood but this appears to occur by impeding vesicular transport.81
The potential role of resistin in cardiac pathobiology has not been extensively studied, although a few studies have been carried out to assess the e ect of resistin on the ischemic and reperfused heart with contradictory results. In one report, resistin depressed functional recovery from ischemia in isolated perfused rat hearts, an e ect which appeared to be dependent on NF-kB activity.91 In contrast, resistin reduced infarct size in mice subjected to coronary artery occlusion and reperfusion.92 These authors also demonstrated that resistin improved functional recovery of isolated mouse hearts and reduced infarct size and proposed that the salutary e ect of resistin occurs via a PI3K/ Akt/PKC pathway. The obvious discrepancy between the two studies is di cult to explain at present but may reflect di erent concentrations of resistin, di erences in experimental model or species diversity.
4.9 Apelin
Apelin is an adipokine that was found to be the endogenous ligand for the G protein-coupled APJ receptor. Apelin has been shown to exert potent