Collectively, our data show that high-fat diet-induced obesity resulted in impaired cardiomyocyte function, upregulated Foxo3a transcription factor and mitochondrial damage without overt lipotoxicity or apoptosis.

Abstract-Leptin regulates cardiovascular function. Leptin levels are elevated in obesity and hypertension and may play a role in cardiovascular dysfunctions in these comorbidities. This study was designed to determine the influence of hypertension on the cardiac contractile response of leptin. Mechanical and intracellular Ca 2ϩ properties were evaluated using an IonOptix system in ventricular myocytes from spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats. The contractile properties included peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR 90 , ϮdL/dt), and fura-fluorescence intensity change (⌬FFI). NO and nitric oxide synthase (NOS) activity were assessed by the Griess and the 3 H-arginine/citrulline conversion assays, respectively. The leptin receptor (Ob-R) and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway were evaluated by Western blot analysis. SHR animals displayed significantly elevated blood pressure and plasma leptin levels. Leptin elicited a concentration-dependent inhibition of PS and ⌬FFI in WKY, but not in SHR myocytes. Leptin did not affect TPS, TR 90 , or Ϯ dL/dt. The difference in leptin-induced contractile response between the WKY and the SHR groups was abolished by the NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME), but not by elevated extracellular Ca 2ϩ . Either the JAK2 inhibitor AG-490 or the mitogen-activated protein (MAP) kinase inhibitor SB203580 abrogated the leptin-induced response in the WKY myocytes, whereas AG-490 unmasked a negative response in PS in the SHR myocytes. SHR myocytes displayed similar Ob-R protein abundance and basal NO levels, a blunted leptin-induced increase in NOS activity as well as enhanced basal STAT3 levels compared with the WKY group. These data indicate that the leptin-induced cardiac contractile response is abolished by spontaneous hypertension, possibly because of mechanisms involving altered JAK/STAT, MAP kinase signaling, and NO response. Key Words: signal transduction Ⅲ hypertension, obesity Ⅲ myocytes Ⅲ cardiac function Ⅲ kinase Ⅲ nitric oxide E pidemiological evidence revealed that over 60% of US adults are considered overweight. 1,2 Obesity is shown to predispose the development of various comorbidities such as hypertension, diabetes, and dyslipidemia. 2,3 Both clinical and experimental evidence has implicated hypertension as the most common comorbidity associated with obesity. 2 Although hypertension and obesity often exist concurrently, leading to ventricular dysfunction, obesity itself is known to enhance the development of other risk factors, such as hypertension and dyslipidemia. 4,5 Leptin, the obesity gene (ob) product, regulates energy metabolism and expenditure. Leptin enhances sympathetic nervous activity, 6 which may be directly associated with increased body fat composition. 7-9 Leptin infusion was shown to reduce blood pressure and heart rate, which may be reversed by nitric oxide synthase (NOS) inhibition. 10,11 Recent...

These data suggest that increased cardiac acetaldehyde exposure due to ADH transgene may play an important role in cardiac contractile dysfunctions associated with lipid and protein damage after alcohol intake.