Protective role of adiponectin in volume overload-induced heart failure

Abstract

Heart failure (HF) is approaching epidemic proportions in United States. Adiponectin is a protein hormone that plays an important role in modulating glucose uptake and fatty acid β-oxidation in the heart. It has been well documented that adiponectin is able to exert protective effects on the ventricular remodeling following pressure overload and myocardial ischemia. However, the potential effect of adiponectin in volume-overload heart failure has not been reported. In addition, no study is available focusing on the potential role of adiponectin in the electrophysiological remodeling following pathological conditions. To investigate the potential effect of adiponectin on ventricular contractile dysfunction following volume overload, we used infrarenal aorta-vena cava fistula surgery to create cardiac volume overload on rats. Our data indicated a progressive reduction of serum adiponectin level with the development of volume overload-induced heart failure. In ventricular myocytes isolated from 12-week Fistula rats, protein expression of APN, AdipoR1, AdipoR2 and T-cadherin were decreased, and AMPK activity was reduced. Consistent with these, myocytes exhibited significant depression in cell shortening and intracellular Ca2+ transient. In vivo supplementation of APN significantly increased APN serum levels, and prevented the depression of myocyte contractile performance following 12-week fistula. Moreover, in vitro treatment with APN also significantly improved myocyte contractility and intracellular Ca2+ transient from 12-week fistula rat. Furthermore, we analyzed the potential role of APN on the ventricular electrophysiological remodeling secondary to volume overload. Results showed that the duration of action potential was prolonged in ventricular myocytes following 10-week fistula, which was reflected by the lengthened QT interval on the surface ECG. The prolongation of action potential duration was correlated with a depression of Ito function as well as a decrease of Ito channel component expression in ventricular myocytes at 10 weeks post-fistula. In addition, the protein level of tumor necrosis factor-α (TNF-α) was significantly increased in ventricular myocytes at 10 weeks post-fistula. However, supplementation of Ad-APN increased the protein levels of Ito channel components and reversed Ito channel function in ventricular myocytes following 10-week fistula. This further restored the duration of action potential in ventricular myocytes and the QT interval on the ECG back to the normal. In addition, the administration of Ad-APN significantly reduced the protein level of TNF-α in ventricular myocytes even following 10-week fistula. These results indicated that APN can prevent the volume overload-induced ventricular electrophysiological remodeling via a decreased production of TNF-α.