Abstract

Currently, there remains a great need to elucidate the molecular mechanism of acute myocardial infarction in order to facilitate the development of novel therapy. Inhibitor of apoptosis-stimulating protein of p53 (iASPP) is a member of the ASPP family proteins and an evolutionarily preserved inhibitor of p53 that is involved in many cellular processes, including apoptosis of cancer cells. The purpose of this study was to investigate the possible role of iASPP in acute myocardial infarction. The protein level of iASPP was markedly reduced in the ischemic hearts in vivo and hydrogen peroxide-exposed cardiomyocytes in vitro. Overexpression of iASPP reduced the infarct size and cardiomyocyte apoptosis of mice subjected to 24 h of coronary artery ligation. Echocardiography showed that cardiac function was improved as indicated by the increase in ejection fraction and fractional shortening. In contrast, knockdown of iASPP exacerbated cardiac injury as manifested by impaired cardiac function, increased infarct size, and apoptosis rate. Mechanistically, overexpression of iASPP inhibited, while knockdown of iASPP increased the expressions of p53 and Bax, the key regulators of apoptosis. Taken together, our results suggested that iASPP is an important regulator of cardiomyocyte apoptosis, which represents a potential target in the therapy of myocardial infarction.

中文翻译：

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iASPP 通过抑制 p53 表达和心肌细胞凋亡来保护心脏免受缺血损伤

 抽象的

目前，仍然非常需要阐明急性心肌梗死的分子机制，以促进新疗法的开发。 p53 凋亡刺激蛋白抑制剂 (iASPP) 是 ASPP 家族蛋白的成员，也是进化上保留的 p53 抑制剂，参与许多细胞过程，包括癌细胞的凋亡。本研究的目的是探讨 iASPP 在急性心肌梗死中的可能作用。体内缺血心脏和体外过氧化氢暴露的心肌细胞中iASPP的蛋白水平显着降低。 iASPP 的过度表达减少了冠状动脉结扎 24 小时小鼠的梗死面积和心肌细胞凋亡。超声心动图显示，射血分数和缩短分数的增加表明心功能得到改善。相反，iASPP 的敲低会加剧心脏损伤，表现为心脏功能受损、梗塞面积增加和细胞凋亡率增加。从机制上讲，iASPP 的过表达会抑制细胞凋亡的关键调节因子 p53 和 Bax 的表达，而 iASPP 的敲除会增加 p53 和 Bax 的表达。综上所述，我们的结果表明 iASPP 是心肌细胞凋亡的重要调节因子，是心肌梗死治疗的潜在靶点。