Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY 82071, USA.
Basic Res Cardiol. 2013 Mar;108(2):335. doi: 10.1007/s00395-013-0335-3. Epub 2013 Feb 5.
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.
心脏衰老表现为心脏重构和收缩功能障碍，尽管确切机制仍不清楚。本研究旨在探讨内皮素-1 (ET-1) 在与衰老相关的心肌形态和收缩缺陷中的作用。在年轻（5-6 个月）和年老（26-28 个月）C57BL/6 野生型和心肌细胞特异性 ET(A)受体敲除（ETAKO）小鼠中评估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 小鼠的存活率提高。衰老增加了 ET-1 和 Ang II 的血浆水平，损害了心脏功能（缩短分数、心肌细胞峰值缩短、缩短/再伸长的最大速度和再伸长延长）和细胞内 Ca(2+)处理（减少细胞内 Ca(2+)释放和衰减），除了 ET-1 和 Ang II 水平外，这些作用都因 ETAKO 而得到改善。组织学检查显示，与 C57 小鼠衰老相关的心肌细胞肥大和间质纤维化，在 ETAKO 小鼠中得到缓解。衰老促进 ROS 生成、蛋白损伤、内质网应激，上调 GATA4、ANP、NFATc3 和自噬体 cargo 蛋白 p62，下调细胞内 Ca(2+)调节蛋白 SERCA2a 和磷蛋白以及自噬标记物 Beclin-1、Atg7、Atg5 和 LC3BII，这些蛋白都被 ETAKO 下调。ET-1 触发自噬减少和体外肥大标志物增加，该作用可被 ET(A)受体拮抗剂 BQ123 和自噬诱导剂雷帕霉素逆转。ET(A)受体拮抗而非 ET(B)受体拮抗可挽救心脏衰老，而自噬抑制则可消除这种作用。总之，我们的数据表明，心脏 ET(A)受体消融可防止与衰老相关的心肌重构和收缩功能障碍，可能通过自噬调节。
