TY - JOUR
T1 - Cardiomyocyte-specific deletion of endothelin receptor A rescues aging-associated cardiac hypertrophy and contractile dysfunction
T2 - Role of autophagy
AU - Ceylan-Isik, Asli F.
AU - Dong, Maolong
AU - Zhang, Yingmei
AU - Dong, Feng
AU - Turdi, Subat
AU - Nair, Sreejayan
AU - Yanagisawa, Masashi
AU - Ren, Jun
N1 - Funding Information:
The authors wish to thank Miss Haoyu Zhao from University of Wyoming for her assistance in data analysis. This work was supported by NIH/NCRR P20 RR016474 and P20 GM103432.
PY - 2013/1/1
Y1 - 2013/1/1
N2 - 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 cardiomyocytespecific ETA 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 Ca2+ 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 Ca2+ 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 ETA receptor antagonist BQ123 and the autophagy inducer rapamycin. Antagonism of ETA, but not ETB receptor, rescued cardiac aging, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ETA receptor ablation protects against aging-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation.
AB - 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 cardiomyocytespecific ETA 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 Ca2+ 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 Ca2+ 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 ETA receptor antagonist BQ123 and the autophagy inducer rapamycin. Antagonism of ETA, but not ETB receptor, rescued cardiac aging, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ETA receptor ablation protects against aging-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation.
KW - Autophagy
KW - Cardiomyocyte
KW - Contraction
KW - ET receptor
KW - Morphology
KW - Myocardial
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U2 - 10.1007/s00395-013-0335-3
DO - 10.1007/s00395-013-0335-3
M3 - Article
C2 - 23381122
AN - SCOPUS:84873377605
SN - 0300-8428
VL - 108
JO - Basic Research in Cardiology
JF - Basic Research in Cardiology
IS - 2
M1 - 335
ER -