Molecular and Cellular Mechanisms Underlying the Cardiac Hypertrophic and Pro-Remodelling Effects of Leptin.

Since its initial discovery in 1994, the adipokine leptin has received extensive interest as an important satiety factor and regulator of energy expenditure. Although produced primarily by white adipocytes, leptin can be synthesized by numerous tissues including those comprising the cardiovascular system. Cardiovascular function can thus be affected by locally produced leptin via an autocrine or paracrine manner but also by circulating leptin. Leptin exerts its effects by binding to and activating specific receptors, termed ObRs or LepRs, belonging to the Class I cytokine family of receptors of which six isoforms have been identified. Although all ObRs have identical intracellular domains, they differ substantially in length in terms of their extracellular domains, which determine their ability to activate cell signalling pathways. The most important of these receptors in terms of biological effects of leptin is the so-called long form (ObRb), which possesses the complete intracellular domain linked to full cell signalling processes. The heart has been shown to express ObRb as well as to produce leptin. Leptin exerts numerous cardiac effects including the development of hypertrophy likely through a number of cell signaling processes as well as mitochondrial dynamics, thus demonstrating substantial complex underlying mechanisms. Here, we discuss mechanisms that potentially mediate leptin-induced cardiac pathological hypertrophy, which may contribute to the development of heart failure.

Probiotics as potential treatments to reduce myocardial remodelling and heart failure via the gut-heart axis: State-of-the-art review.

Probiotics are considered to represent important modulators of gastrointestinal health through increased colonization of beneficial bacteria thus altering the gut microflora. Although these beneficial effects of probiotics are now widely recognized, emerging evidence suggests that alterations in the gut microflora also affect numerous other organ systems including the heart through a process generally referred to as the gut-heart axis. Moreover, cardiac dysfunction such as that seen in heart failure can produce an imbalance in the gut flora, known as dysbiosis, thereby further contributing to cardiac remodelling and dysfunction. The latter occurs by the production of gut-derived pro-inflammatory and pro-remodelling factors which exacerbate cardiac pathology. One of the key contributors to gut-dependent cardiac pathology is trimethylamine N-oxide (TMAO), a choline and carnitine metabolic by-product first synthesized as trimethylamine which is then converted into TMAO by a hepatic flavin-containing monooxygenase. The production of TMAO is particularly evident with regular western diets containing high amounts of both choline and carnitine. Dietary probiotics have been shown to reduce myocardial remodelling and heart failure in animal models although the precise mechanisms for these effects are not completely understood. A large number of probiotics have been shown to possess a reduced capacity to synthesize gut-derived trimethylamine and therefore TMAO thereby suggesting that inhibition of TMAO is a factor mediating the beneficial cardiac effects of probiotics. However, other potential mechanisms may also be important contributing factors. Here, we discuss the potential benefit of probiotics as effective therapeutic tools for attenuating myocardial remodelling and heart failure.

Chemical components of ginseng, their biotransformation products and their potential as treatment of hypertension.

Ginseng is an ancient perennial herb belonging to the family Araliaceae and genus Panax which has been used for medical therapeutics for thousands of years, particularly in China and other Asian cultures although increasing interest in ginseng has recently emerged in western societies. Ginseng is a complex substance containing dozens of bioactive and potentially effective therapeutic compounds. Among the most studied are the ginsenosides, which are triterpene saponins possessing a wide array of potential therapeutic effects for many conditions. The quantity and type of ginsenoside vary greatly depending on ginseng species and their relative quantity in a given ginseng species is greatly affected by extraction processes as well as by subjecting ginseng to various procedures such as heating. Adding to the complexity of ginsenosides is their ability to undergo biotransformation to bioactive metabolites such as compound K by enteric bacteria following ingestion. Many ginsenosides exert vasodilatating effects making them potential candidates for the treatment of hypertension. Their vascular effects are likely dependent on eNOS activation resulting in the increased production of NO. One proposed end-mechanism involves the activation of calcium-activated potassium channels in vascular smooth cells resulting in reduced calcium influx and a vasodilatating effect, although other mechanisms have been proposed as discussed in this review.

Inhibition of angiotensin II-induced hypertrophy and cardiac dysfunction by North American ginseng (Panax quinquefolius).

We determined whether North American ginseng (Panax quinquefolius L.) mitigates the effect of angiotensin II on hypertrophy and heart failure. Angiotensin II (0.3 mg/kg) was administered to rats for 2 or 4 weeks in the presence or absence of ginseng pretreatment. The effect of ginseng (10 µg/mL) on angiotensin II (100 nM) - induced hypertrophy was also determined in neonatal rat ventricular myocytes. We also determined effects of ginseng on fatty acid and glucose oxidation by measuring gene and protein expression levels of key factors. Angiotensin II treatment for 2 and 4 weeks induced cardiac hypertrophy as evidenced by increased heart weights, as well as the upregulation of the hypertrophy-related fetal gene expression levels, with all effects being abolished by ginseng. Ginseng also reduced abnormalities in left ventricular function as well as the angiotensin II-induced increased blood pressure. In myocytes, ginseng abolished the hypertrophic response to angiotensin II as assessed by surface area and gene expression of molecular markers of hypertrophy. Ginseng modulated angiotensin II-induced abnormalities in gene expression and protein levels of CD36, CPT1M, Glut4, and PDK4 in vivo and in vitro. In conclusion, ginseng suppresses angiotensin II-induced cardiac hypertrophy and dysfunction which is related to normalization of fatty acid and glucose oxidation.

Leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission.

Cardiac pathology including hypertrophy has been associated with an imbalance between mitochondrial fission and fusion. Generally, well-balanced mitochondrial fission and fusion are essential for proper functions of mitochondria. Leptin is a 16-kDa appetite-suppressing protein which has been shown to induce cardiomyocyte hypertrophy. In the present study, we determined whether leptin can influence mitochondrial fission or fusion and whether this can be related to its hypertrophic effect. Cardiomyocytes treated for 24 h with 3.1 nM leptin (50 ng/ml), a concentration representing plasma levels in obese individuals, demonstrated an increase in surface area and a significant 1.6-fold increase in the expression of the ß-myosin heavy chain. Mitochondrial staining with MitoTracker Green dye showed elongated structures in control cells with an average length of 4.5 µm. Leptin produced a time-dependent increase in mitochondrial fragmentation with decreasing mitochondrial length. The hypertrophic response to leptin was also associated with increased protein levels of the mitochondrial fission protein dynamin-related protein1 (Drp1) although gene expression of Drp1 was unaffected possibly suggesting post-translational modifications of Drp1. Indeed, leptin treatment was associated with decreased levels of phosphorylated Drp1 and increased translocation of Drp1 to the mitochondria thereby demonstrating a pro-fission effect of leptin. As calcineurin may dephosphorylate Drp1, we determined the effect of a calcineurin inhibitor, FK506, which prevented leptin-induced hypertrophy as well as mitochondrial fission and mitochondrial dysfunction. In conclusion, our data show that leptin-induced cardiomyocyte hypertrophy is associated with enhanced mitochondrial fission via a calcineurin-mediated pathway. The ability of leptin to stimulate mitochondrial fission may be important in understanding the role of this protein in cardiac pathology especially that related to mitochondrial dysfunction.

Ginseng for the treatment of diabetes and diabetes-related cardiovascular complications: a discussion of the evidence 1.

Diabetes mellitus (DM) is a chronic metabolic disorder associated with elevated blood glucose levels due either to insufficient insulin production (type 1 DM) or to insulin resistance (type 2 DM). The incidence of DM around the world continues to rise dramatically with more than 400 million cases reported today. Among the most serious consequences of chronic DM are cardiovascular complications that can have deleterious effects. Although numerous treatment options are available, including both pharmacological and nonpharmacological, there is substantial emerging interest in the use of traditional medicines for the treatment of this condition and its complications. Among these is ginseng, a medicinal herb that belongs to the genus Panax and has been used for thousands of years as a medicinal agent especially in Asian cultures. There is emerging evidence from both animal and clinical studies that ginseng, ginseng constituents including ginsenosides, and ginseng-containing formulations can produce beneficial effects in terms of normalization of blood glucose levels and attenuation of cardiovascular complications through a multiplicity of mechanisms. Although more research is required, ginseng may offer a useful therapy for the treatment of diabetes as well as its complications.

Cardioprotection by ginseng: experimental and clinical evidence and underlying mechanisms.

Protection of the ischemic and reperfused myocardium represents a major therapeutic challenge. Translating results from animal studies to the clinical setting has been disappointing, yet the need for effective intervention, particularly to limit heart damage following infarction or surgical procedures such as coronary artery bypass grafting, is substantial. Among the many compounds touted as cardioprotective agents is ginseng, a medicinal herb belonging to the genus Panax, which has been used as a medicinal agent for thousands of years, particularly in Asian societies. The biological actions of ginseng are very complex and reflect composition of many bioactive components, although many of the biological and therapeutic effects of ginseng have been attributed to the presence of steroid-like saponins termed ginsenosides. Both ginseng and many ginsenosides have been shown to exert cardioprotective properties in experimental models. There is also clinical evidence that traditional Chinese medications containing ginseng exert cardioprotective properties, although such clinical evidence is less robust primarily owing to the paucity of large-scale clinical trials. Here, we discuss the experimental and clinical evidence for ginseng, ginsenosides, and ginseng-containing formulations as cardioprotective agents against ischemic and reperfusion injury. We further discuss potential mechanisms, particularly as these relate to antioxidant properties.

Treatment of the cardiac hypertrophic response and heart failure with ginseng, ginsenosides, and ginseng-related products.

Heart failure is a major medical and economic burden throughout the world. Although various treatment options are available to treat heart failure, death rates in both men and women remain high. Potential adjunctive therapies may lie with use of herbal medications, many of which possess potent pharmacological properties. Among the most widely studied is ginseng, a member of the genus Panax that is grown in many parts of the world and that has been used as a medical treatment for a variety of conditions for thousands of years, particularly in Asian societies. There are a number of ginseng species, each possessing distinct pharmacological effects due primarily to differences in their bioactive components including saponin ginsenosides and polysaccharides. While experimental evidence for salutary effects of ginseng on heart failure is robust, clinical evidence is less so, primarily due to a paucity of large-scale well-controlled clinical trials. However, there is evidence from small trials that ginseng-containing Chinese medications such as Shenmai can offer benefit when administered as adjunctive therapy to heart failure patients. Substantial additional studies are required, particularly in the clinical arena, to provide evidence for a favourable effect of ginseng in heart failure patients.

North American ginseng (Panax quinquefolius) suppresses ß-adrenergic-dependent signalling, hypertrophy, and cardiac dysfunction.

There is increasing evidence for a beneficial effect of ginseng on cardiac pathology. Here, we determined whether North American ginseng can modulate the deleterious effects of the ß-adrenoceptor agonist isoproterenol on cardiac hypertrophy and function using in vitro and in vivo approaches. Isoproterenol was administered for 2 weeks at either 25 mg/kg per day or 50 mg/kg per day (ISO25 or ISO50) via a subcutaneously implanted osmotic mini-pump to either control rats or those receiving ginseng (0.9 g/L in the drinking water ad libitum). Isoproterenol produced time- and dose-dependent left ventricular dysfunction, although these effects were attenuated by ginseng. Improved cardiac functions were associated with reduced heart masses, as well as prevention in the upregulation of the hypertrophy-related fetal gene expression. Lung masses were similarly attenuated, suggesting reduced pulmonary congestion. In in vitro studies, ginseng (10 µg/mL) completely suppressed the hypertrophic response to 1 µmol/L isoproterenol in terms of myocyte surface area, as well as reduction in the upregulation of fetal gene expression. These effects were associated with attenuation in both protein kinase A and cAMP response element-binding protein phosphorylation. Ginseng attenuates adverse cardiac adrenergic responses and, therefore, may be an effective therapy to reduce hypertrophy and heart failure associated with excessive catecholamine production.

Cardiomyocyte Antihypertrophic Effect of Adipose Tissue Conditioned Medium from Rats and Its Abrogation by Obesity is Mediated by the Leptin to Adiponectin Ratio.

White adipocytes are known to function as endocrine organs by secreting a plethora of bioactive adipokines which can regulate cardiac function including the development of hypertrophy. We determined whether adipose tissue conditioned medium (ATCM) generated from the epididymal regions of normal rats can affect the hypertrophic response of cultured rat ventricular myocytes to endothelin-1 (ET-1) administration. Myocytes were treated with ET-1 (10 nM) for 24 hours in the absence or presence of increasing ATCM concentrations. ATCM supressed the hypertrophic response to ET-1 in a concentration-dependent manner, an effect enhanced by the leptin receptor antagonist and attenuated by an antibody against the adiponectin AdipoR1 receptor. Antihypertrophic effects were also observed with ATCM generated from perirenal-derived adipose tissue. However, this effect was absent in ATCM from adipose tissue harvested from corpulent JCR:LA-cp rats. Detailed analyses of adipokine content in ATCM from normal and corpulent rats revealed no differences in the majority of products assayed, although a significant increase in leptin concentrations concomitant with decreased adiponectin levels was observed, resulting in a 11 fold increase in the leptin to adiponectin ratio in ATCM from JCR:LA-cp. The antihypertrophic effect of ATCM was associated with increased phosphorylation of AMP-activated protein kinase (AMPK), an effect abrogated by the AdipoR1 antibody. Moreover, the antihypertrophic effect of ATCM was mimicked by an AMPK activator. There was no effect of ET-1 on mitogen-activated protein kinase (MAPK) activities 24 hour after its addition either in the presence or absence of ATCM. Our study suggests that adipose tissue from healthy subjects exerts antihypertrophic effects via an adiponectin-dependent pathway which is impaired in obesity, most likely due to adipocyte remodelling resulting in enhanced leptin and reduced adiponectin levels.

Myocardial Hypertrophic Remodeling and Impaired Left Ventricular Function in Mice with a Cardiac-Specific Deletion of Janus Kinase 2.

The Janus kinase (JAK) system is involved in numerous cell signaling processes and is highly expressed in cardiac tissue. The JAK isoform JAK2 is activated by numerous factors known to influence cardiac function and pathologic conditions. However, although abundant, the role of JAK2 in the regulation or maintenance of cardiac homeostasis remains poorly understood. Using the Cre-loxP system, we generated a cardiac-specific deletion of Jak2 in the mouse to assess the effect on cardiac function with animals followed up for a 4-month period after birth. These animals had marked mortality during this period, although at 4 months mortality in male mice (47%) was substantially higher compared with female mice (30%). Both male and female cardiac Jak2-deleted mice had hypertrophy, dilated cardiomyopathy, and severe left ventricular dysfunction, including a marked reduction in ejection fractions as assessed by serial echocardiography, although the responses in females were somewhat less severe. Defective cardiac function was associated with altered protein levels of sarcoplasmic reticulum calcium-regulatory proteins particularly in hearts from male mice that had depressed levels of SERCA2 and phosphorylated phospholamban. In contrast, SERCA2 was unchanged in hearts of female mice, whereas phosphorylated phospholamban was increased. Our findings suggest that cardiac JAK2 is critical for maintaining normal heart function, and its ablation produces a severe pathologic phenotype composed of myocardial remodeling, heart failure, and pronounced mortality.

Identification of functional leptin receptors expressed in ventricular mitochondria.

Leptin is a 16 kDa pro-satiety peptide produced primarily not only by white adipocytes but also by numerous other tissues including the heart. Circulating leptin exerts its effect through specific receptors, although its principle actions are dependent on the activation of the long form of the leptin receptor, termed OBRb. As leptin is also produced within the cardiomyocyte, we hypothesized that the peptide can also exert effects by targeting intracellular sites. Accordingly, we determined whether cardiac mitochondria express functional leptin receptors. The presence of mitochondrial OBRb was identified through Western blotting of isolated mitochondria, immunofluorescence as well as immunogold labeling with electron microscopy. Although leptin had no direct effect on mitochondrial integrity, it profoundly enhanced the ability of calcium to induce mitochondrial swelling, an effect partially reversed by an OBR antagonist. 24 h exposure to leptin (50 ng/ml) was without effect on mitochondria in cultured neonatal rat ventricular myocytes in contrast to leptin tagged with a 10 amino acid membrane translocation sequence which significantly induced mitochondrial permeability transition pore opening, whereas both leptins produced a hypertrophic response. Our results therefore show that mitochondria express functional OBR which may be of importance toward understanding the role of intracellularly derived leptin in cardiac physiology and pathology.

Early and transient sodium-hydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation.

Na(+)/H(+) exchanger 1 (NHE-1) inhibition attenuates the hypertrophic response and heart failure in various experimental models. As the hypertrophic program is rapidly initiated following insult, we investigated whether early and transient administration of a NHE-1 inhibitor will exert salutary effects on cardiomyocyte hypertrophy or heart failure using both in vitro and in vivo approaches. Neonatal cardiomyocytes were treated with the novel, potent, and highly specific NHE-1 inhibitor BIX (N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine; 100 nM) for 1 hour in the presence of 10 µM phenylephrine, after which the cells were maintained for a further 23 hours in the absence of NHE-1 inhibition. One-hour treatment with the NHE-1 inhibitor prevented phenylephrine-induced hypertrophy, which was associated with prevention of activation of calcineurin, a key component of the hypertrophic process. Experiments were then performed in rats subjected to coronary artery ligation, in which the NHE-1 inhibitor was administered immediately after infarction for a 1-week period followed by a further 5 weeks of sustained coronary artery occlusion in the absence of drug treatment. This approach significantly attenuated left ventricular hypertrophy and improved both left ventricular systolic and diastolic dysfunction, which was also associated with inhibition of calcineurin activation. Our findings indicate that early and transient administration of an NHE-1 inhibitor bestows subsequent inhibition of cardiomyocyte hypertrophy in culture as well as cardiac hypertrophy and heart failure in vivo, suggesting a critical early NHE-1-dependent initiation of the hypertrophic program. The study also suggests a preconditioning-like phenomenon in preventing hypertrophy and heart failure by early and transient NHE-1 inhibition.

CD73-TNAP crosstalk regulates the hypertrophic response and cardiomyocyte calcification due to α1 adrenoceptor activation.

Cluster of differentiation 73 (CD73) is an ecto-5' nucleotidase which catalyzes the conversion of AMP to adenosine. One of the many functions of adenosine is to suppress the activity of tissue nonspecific alkaline phosphatase (TNAP), an enzyme important in regulating intracellular calcification. Since myocardial calcification is associated with various cardiac disease states, we studied the individual roles and crosstalk between CD73 and TNAP in regulating myocyte responses to the α1 adrenoceptor agonist phenylephrine in terms of calcification and hypertrophy. Cultured neonatal rat cardiomyocytes were treated with 10 µM phenylephrine for 24 h in the absence or presence of the stable adenosine analog 2-chloro-adenosine, the TNAP inhibitor tetramisole or the CD73 inhibitor α,ß-methylene ADP. Phenylephrine produced marked hypertrophy as evidenced by significant increases in myocyte surface area and ANP gene expression, as well as calcification determined by Alizarin Red S staining. These responses were associated with reduced CD73 gene and protein expression and CD73 activity. Conversely, TNAP expression and activity were significantly increased although both were suppressed by 2-chloro-adenosine. CD73 inhibition alone significantly reduced myocyte-derived adenosine levels by >50 %, and directly induced hypertrophy and calcification in the absence of phenylephrine. These responses and those to phenylephrine were abrogated by TNAP inhibition. We conclude that TNAP contributes to the hypertrophic effect of phenylephrine, as well as its ability to produce cardiomyocyte calcification. These responses are minimized by CD73-dependent endogenously produced adenosine.

Probiotic administration attenuates myocardial hypertrophy and heart failure after myocardial infarction in the rat.

BACKGROUND: Probiotics are extensively used to promote gastrointestinal health, and emerging evidence suggests that their beneficial properties can extend beyond the local environment of the gut. Here, we determined whether oral probiotic administration can alter the progression of postinfarction heart failure. METHODS AND RESULTS: Rats were subjected to 6 weeks of sustained coronary artery occlusion and administered the probiotic Lactobacillus rhamnosus GR-1 or placebo in the drinking water ad libitum. Culture and 16s rRNA sequencing showed no evidence of GR-1 colonization or a significant shift in the composition of the cecal microbiome. However, animals administered GR-1 exhibited a significant attenuation of left ventricular hypertrophy based on tissue weight assessment and gene expression of atrial natriuretic peptide. Moreover, these animals demonstrated improved hemodynamic parameters reflecting both improved systolic and diastolic left ventricular function. Serial echocardiography revealed significantly improved left ventricular parameters throughout the 6-week follow-up period including a marked preservation of left ventricular ejection fraction and fractional shortening. Beneficial effects of GR-1 were still evident in those animals in which GR-1 was withdrawn at 4 weeks, suggesting persistence of the GR-1 effects after cessation of therapy. Investigation of mechanisms showed a significant increase in the leptin:adiponectin plasma concentration ratio in rats subjected to coronary ligation, which was abrogated by GR-1. Metabonomic analysis showed differences between sham control and coronary artery ligated hearts particularly with respect to preservation of myocardial taurine levels. CONCLUSIONS: The study suggests that probiotics offer promise as a potential therapy for the attenuation of heart failure.

Prevention of RhoA activation and cofilin-mediated actin polymerization mediates the antihypertrophic effect of adenosine receptor agonists in angiotensin II- and endothelin-1-treated cardiomyocytes.

Adenosine receptor activation has been shown to be associated with diminution of cardiac hypertrophy and it has been suggested that endogenously produced adenosine may serve to blunt pro-hypertrophic processes. In the present study, we determined the effects of two pro-hypertrophic stimuli, angiotensin II (Ang II, 100 nM) and endothelin-1 (ET-1, 10 nM) on Ras homolog gene family, member A (RhoA)/Rho-associated, coiled-coil containing protein kinase (ROCK) activation in cultured neonatal rat ventricular myocytes and whether the latter serves as a target for the anti-hypertrophic effect of adenosine receptor activation. Both hypertrophic stimuli potently increased RhoA activity with peak activation occurring 15-30 min following agonist addition. These effects were associated with significantly increased phosphorylation (inactivation) of cofilin, a downstream mediator of RhoA, an increase in actin polymerization, and increased activation and nuclear import of p38 mitogen activated protein kinase. The ability of both Ang II and ET-1 to activate the RhoA pathway was completely prevented by the adenosine A1 receptor agonist N (6)-cyclopentyladenosine, the A2a receptor agonist 2-p-(2-carboxyethyl)-phenethylamino-5'-N-ethylcarboxamidoadenosine, the A3 receptor agonist N (6)-(3-iodobenzyl)adenosine-5'-methyluronamide as well as the nonspecific adenosine analog 2-chloro adenosine. All effects of specific receptor agonists were prevented by their respective receptor antagonists. Moreover, all adenosine agonists prevented either Ang II- or ET-1-induced hypertrophy, a property shared by the RhoA inhibitor Clostridium botulinum C3 exoenzyme, the ROCK inhibitor Y-27632 or the actin depolymerizing agent latrunculin B. Our study therefore demonstrates that both Ang II and ET-1 can activate the RhoA pathway and that prevention of the hypertrophic response to both agonists by adenosine receptor activation is mediated by prevention of RhoA stimulation and actin polymerization.

Leptin as a cardiac pro-hypertrophic factor and its potential role in the development of heart failure.

The identification of the adipocyte as a source of production of biologically-active peptides has materialized into an active area of research related to the role of these peptides in physiology and pathophysiology. Moreover, this research has resulted in the identification of the adipocyte as an endocrine organ producing potent bioactive compounds. An increasing number of these adipokines are being identified, the first of which was leptin, a product of the obesity gene whose primary function is to act as a satiety factor but which is now known to exert a myriad of effects. It is now recognized that virtually all adipokines produce effects on numerous organ systems including the heart and many of these, including leptin, are produced by cardiac tissue. Here we focus primarily on the diverse effects of leptin on the heart especially as it pertains to hypertrophy and discuss the potential cell signaling mechanisms underlying their actions. Current evidence suggests that leptin is a cardiac hypertrophic factor and from clinical studies there is evidence that hyperleptinemia is associated with cardiovascular risk especially as it pertains to heart failure. While more substantial research needs to be carried out, leptin may represent a potential link between obesity, which is associated with hyperleptinemia, and increased cardiovascular risk.

The potential contribution of circulating and locally produced leptin to cardiac hypertrophy and failure.

Leptin is a 16 kDa peptide that was first identified in 1994 through positional cloning of the mouse obesity gene. Although the primary function of leptin is to act a satiety factor through its actions on the hypothalamus, it is now widely recognized that leptin can exert effects on many other organs through activation of its receptors, which are ubiquitously expressed. Leptin is secreted primarily by white adipocytes, but it is also produced by other tissues including the heart where it can exert effects in an autocrine or paracrine manner. One of these effects involves the induction of cardiomyocyte hypertrophy, which appears to occur via multiple cell signalling mechanisms. As adipocytes are the primary site of leptin production, plasma leptin concentrations are generally positively related with body mass index and the degree of adiposity. However, hyperleptinemia is also associated with cardiovascular disease, including heart failure, in the absence of obesity. Here we review the potential role of leptin in heart disease, particularly pertaining to its potential contribution to myocardial remodelling and heart failure, as well as the underlying mechanisms. We further discuss potential interactions between leptin and another adipokine, adiponectin, and the potential implications of this interaction in terms of fully understanding leptin's effects.

Identification of fat mass and obesity associated (FTO) protein expression in cardiomyocytes: regulation by leptin and its contribution to leptin-induced hypertrophy.

The recently-identified fat mass and obesity-associated (FTO) protein is associated with various physiological functions including energy and body weight regulation. Ubiquitously expressed, FTO was identified in heart homogenates although its function is unknown. We studied whether FTO is specifically expressed within the cardiac myocyte and its potential role pertaining to the hypertrophic effect of the adipokine leptin. Most experiments were performed using cultured neonatal rat cardiomyocytes which showed nuclei-specific FTO expression. Leptin significantly increased FTO expression which was associated with myocyte hypertrophy although both events were abrogated by FTO knockdown with siRNA. Administration of a leptin receptor antibody to either normal or obese rats significant reduced myocardial FTO protein expression. Responses in cardiomyocytes were accompanied by JAK2/STAT3 activation whereas JAK2/STAT3 inhibition abolished these effects. Expression of the cut-like homeobox 1(CUX1) transcriptional factor was significantly increased by leptin although this was restricted to the cathepsin L-dependent, proteolytically-derived shorter p110CUX1 isoform whereas the longer p200CUX1 protein was not significantly affected. Cathepsin L expression and activity were both significantly increased by leptin whereas a cathepsin L peptide inhibitor or siRNA specific for CUX1 completely prevented the leptin-induced increase in FTO expression. The cathepsin L peptide inhibitor or siRNA-induced knockdown of either CUX1 or FTO abrogated the hypertrophic response to leptin. Two other pro-hypertrophic factors, endothelin-1 or angiotensin II had no effect on FTO expression and FTO knockdown did not alter the hypertrophic response to either agent. This study demonstrates leptin-induced FTO upregulation in cardiomyocytes via JAK2/STAT3- dependent CUX1 upregulation and suggests an FTO regulatory function of leptin. It also demonstrates for the first time a functional role of FTO in the cardiomyocyte.