Cardiomyocyte-specific deletion of endothelin receptor A rescues aging-associated cardiac hypertrophy and contractile dysfunction: role of autophagy.

Cardiac aging is manifested as cardiac remodeling and contractile dysfunction although precise mechanisms remain elusive. This study was designed to examine the role of endothelin-1 (ET-1) in aging-associated myocardial morphological and contractile defects. Echocardiographic and cardiomyocyte contractile properties were evaluated in young (5-6 months) and old (26-28 months) C57BL/6 wild-type and cardiomyocyte-specific ET(A) receptor knockout (ETAKO) mice. Cardiac ROS production and histology were examined. Our data revealed that ETAKO mice displayed an improved survival. Aging increased plasma levels of ET-1 and Ang II, compromised cardiac function (fractional shortening, cardiomyocyte peak shortening, maximal velocity of shortening/relengthening and prolonged relengthening) and intracellular Ca(2+) handling (reduced intracellular Ca(2+) release and decay), the effects of which with the exception of ET-1 and Ang II levels was improved by ETAKO. Histological examination displayed cardiomyocyte hypertrophy and interstitial fibrosis associated with cardiac remodeling in aged C57 mice, which were alleviated in ETAKO mice. Aging promoted ROS generation, protein damage, ER stress, upregulated GATA4, ANP, NFATc3 and the autophagosome cargo protein p62, downregulated intracellular Ca(2+) regulatory proteins SERCA2a and phospholamban as well as the autophagic markers Beclin-1, Atg7, Atg5 and LC3BII, which were ablated by ETAKO. ET-1 triggered a decrease in autophagy and increased hypertrophic markers in vitro, the effect of which were reversed by the ET(A) receptor antagonist BQ123 and the autophagy inducer rapamycin. Antagonism of ET(A), but not ET(B) receptor, rescued cardiac aging, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ET(A) receptor ablation protects against aging-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation.