Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury
Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury
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DOI：
10.1161/circresaha.109.214346
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发表时间：
2010-06-11
影响因子：
20.1
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Naito, Atsuhiko T.;Okada, Sho;Komuro, Issei
基本原理：包括心肌梗死在内的冠心病患者数量不断增加，人们期待着新的治疗策略。心肌梗死后肿瘤抑制蛋白p53在心肌中积聚，导致心肌细胞凋亡，在心力衰竭的进展中起重要作用。目的：我们研究了心肌梗死后p53在心脏中积聚的分子机制，并测试抗p53方法是否对心肌梗死有效。方法和结果：通过表达筛选，我们发现CHIP（carboxyterminal of Hsp 70-interacting protein）是心脏中的内源性p53拮抗剂。CHIP通过泛素化和诱导蛋白酶体降解抑制p53水平。缺氧应激后CHIP转录下调，CHIP蛋白水平的恢复阻止了缺氧应激后p53的积累。体内CHIP过表达可防止心肌梗死后p53积聚和心肌细胞凋亡。热休克蛋白（Hsp）90抑制剂17-烯丙基氨基-17-去甲氧基格尔德霉素（17-AAG）促进CHIP功能，也可在体外和体内阻止p53积聚和心肌细胞凋亡。CHIP介导的p53降解至少是17-AAG.Conclusions的心脏保护作用之一：我们发现，缺氧引起的CHIP水平下调是心肌梗死后心脏中p53积累的原因。降低p53的表达量可防止心肌细胞凋亡，改善心肌梗死后心室重构。我们的结论是，抗p53的方法将是有效的治疗心肌梗死。(Circ Res. 2010; 106：1692-1702）。
Rationale: The number of patients with coronary heart disease, including myocardial infarction, is increasing and novel therapeutic strategy is awaited. Tumor suppressor protein p53 accumulates in the myocardium after myocardial infarction, causes apoptosis of cardiomyocytes, and plays an important role in the progression into heart failure.Objectives: We investigated the molecular mechanisms of p53 accumulation in the heart after myocardial infarction and tested whether anti-p53 approach would be effective against myocardial infarction.Methods and Results: Through expression screening, we found that CHIP (carboxyl terminus of Hsp70-interacting protein) is an endogenous p53 antagonist in the heart. CHIP suppressed p53 level by ubiquitinating and inducing proteasomal degradation. CHIP transcription was downregulated after hypoxic stress and restoration of CHIP protein level prevented p53 accumulation after hypoxic stress. CHIP overexpression in vivo prevented p53 accumulation and cardiomyocyte apoptosis after myocardial infarction. Promotion of CHIP function by heat shock protein (Hsp) 90 inhibitor, 17-allylamino-17-demethoxy geldanamycin (17-AAG), also prevented p53 accumulation and cardiomyocyte apoptosis both in vitro and in vivo. CHIP-mediated p53 degradation was at least one of the cardioprotective effects of 17-AAG.Conclusions: We found that downregulation of CHIP level by hypoxia was responsible for p53 accumulation in the heart after myocardial infarction. Decreasing the amount of p53 prevented myocardial apoptosis and ameliorated ventricular remodeling after myocardial infarction. We conclude that anti-p53 approach would be effective to treat myocardial infarction. (Circ Res. 2010; 106: 1692-1702.)