Abstract 298: Irisin is an Endogenous Negative Regulator of Pathological Cardiac Hypertrophy

Abstract

Cardiac hypertrophy is a common pathophysiological process in various cardiovascular disease which still has no effective therapies. Irisin is a novel myokine mainly secreted by skeletal muscle which is involved in the regulation of energy metabolism. However, its role in cardiac hypertrophy is still unclear. In the present study, we found that serum irisin concentration is significantly elevated in patients with hypertension. Moreover, irisin concentration has strong correlation with left ventricular posterior wall thickness(LVPWT) and intraventricular septal thickness (IVST) which are two major parameters to measure left ventricular hypertrophy. The above results suggested that irisin may be involved in the regulation of pressure overload-induced cardiac hypertrophy. Hence, we further generated transverse aortic constriction-induced cardiac hypertrophy murine model. We found that irisin expression in heart and serum were both elevated in hypertrophic murine hearts. The in vitro study also indicated the angiotensin II treated cardiomyocytes have a higher level of irisin concentration. These data indicated that cardiomyocyte can secret irisin and the irisin concentration is elevated after hypertrophic stimuli. Furthermore, we demonstrated that cardiac hypertrophy was significantly attenuated with improved cardiac function assessed by echocardiography after irisin administration. HE and PSR staining also showed decreased cardiomyocytes size and fibrosis. Mechanistically, we demonstrated that cardiomyocytes treated with ADAM family inhibitor (TAP-2) has a lower irisin level while the expression of irisin precursor (FNDC5) has no obvious alteration. These data implied that FNDC5 was cleaved into irisin, at least partially, in a ADAM family dependent manner. Further we found that irisin administration activates AMPK and subsequently inhibited activation of mTOR. In conclusion, we demonstrated that cardiomyocytes secret irisin in a ADAM family dependent manner, administration of irisin attenuated pressure overload-induced cardiac hypertrophy and fibrosis, improved cardiac function by AMPK-mTOR signaling.