Cardiomyocyte-specific deletion of endothelin receptor A rescues aging-associated cardiac hypertrophy and contractile dysfunction: role of autophagy.
Cardiomyocyte-specific deletion of endothelin receptor A rescues aging-associated cardiac hypertrophy and contractile dysfunction: role of autophagy.
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DOI：
10.1007/s00395-013-0335-3
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发表时间：
2013-03
影响因子：
9.5
通讯作者：
Ren J
中科院分区：
文献类型：
--
作者：
Ceylan-Isik AF;Dong M;Zhang Y;Dong F;Turdi S;Nair S;Yanagisawa M;Ren J
心脏老化表现为心脏重塑和收缩功能障碍，但确切的机制仍然是难以捉摸的。本研究旨在探讨内皮素-1（ET-1）在增龄相关心肌形态学和收缩功能缺陷中的作用。在年轻（5-6个月）和老年（26-28个月）C57 BL/6野生型和心肌细胞特异性ETA受体敲除（ETAKO）小鼠中评价超声心动图和心肌细胞收缩特性。检查心脏ROS产生和组织学。我们的数据显示，ETAKO小鼠显示出改善的存活率。衰老增加了血浆ET-1和Ang II水平，损害了心脏功能（缩短分数、心肌细胞峰值缩短、缩短/再充盈的最大速度和延长的再充盈）和细胞内Ca 2+处理（减少细胞内Ca 2+释放和衰减），ETAKO改善了除ET-1和Ang II水平外的其他效应。组织学检查显示老年C57小鼠心肌细胞肥大和间质纤维化与心脏重塑有关，ETAKO小鼠减轻。衰老促进ROS生成、蛋白质损伤、ER应激、上调GATA 4、ANP、NFATc 3和自噬体货物蛋白p62、下调细胞内Ca 2+调节蛋白SERCA 2a和受磷蛋白以及自噬标记物Beclin-1、Atg 7、Atg 5和LC 3BII，这些都被ETAKO消融。ET-1在体外引起自噬减少和肥大标志物增加，其作用可被ETA受体拮抗剂BQ 123和自噬诱导剂雷帕霉素逆转。ETA而不是ETB受体的拮抗作用挽救了心脏衰老，这被自噬抑制所否定。综上所述，我们的数据表明，心脏ETA受体消融可能通过自噬调节来保护与衰老相关的心肌重塑和收缩功能障碍。
Cardiac ageing 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 ageing-associated myocardial morphological and contractile defects. Echocardiographic and cardiomyocyte contractile properties were evaluated in young (5–6 mo) and old (26–28 mo) C57BL/6 wild-type and cardiomyocyte-specific ETA receptor knockout (ETAKO) mice. Cardiac ROS production and histology were examined. Our data revealed that ETAKO mice displayed an improved survival. Ageing 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 Ca2+ 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. Ageing 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 vitrothe 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 ageing, which was negated by autophagy inhibition. Taken together, our data suggest that cardiac ETA receptor ablation protects against ageing-associated myocardial remodeling and contractile dysfunction possibly through autophagy regulation.
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影响因子：
9.5
作者：
Kakarla, Sunil K.;Fannin, Jacqueline C.;Blough, Eric R.
通讯作者：
Blough, Eric R.
影响因子：
10.8
作者：
Granata, Riccarda;Trovato, Letizia;Ghigo, Ezio
通讯作者：
Ghigo, Ezio
影响因子：
4.8
作者：
Doyle, Alexander;Zhang, Guohua;Li, Yi-Ping
通讯作者：
Li, Yi-Ping
影响因子：
9.5
作者：
Hua, Yinan;Zhang, Yingmei;Ren, Jun
通讯作者：
Ren, Jun
DOI：
10.1152/ajpheart.01071.2006
发表时间：
2007-04-01
影响因子：
4.8
作者：
Boengler, Kerstin;Konietzka, Ina;Schulz, Rainer
通讯作者：
Schulz, Rainer