Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Circ Res. 2010 Jun 11;106(11):1692-702. doi: 10.1161/CIRCRESAHA.109.214346. Epub 2010 Apr 22.
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.
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.
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.
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.
冠心病（包括心肌梗死）患者的数量正在增加，期待新的治疗策略。肿瘤抑制蛋白 p53 在心肌梗死后在心肌中积累，导致心肌细胞凋亡，并在心衰进展中发挥重要作用。
我们研究了心肌梗死后 p53 在心脏中积累的分子机制，并测试了抗 p53 方法是否对心肌梗死有效。
通过表达筛选，我们发现 CHIP（Hsp70 相互作用蛋白羧基末端）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来抑制 p53 水平。在缺氧应激下，CHIP 转录下调，恢复 CHIP 蛋白水平可防止缺氧应激后 p53 积累。体内过表达 CHIP 可防止心肌梗死后 p53 积累和心肌细胞凋亡。热休克蛋白（Hsp）90 抑制剂 17- 烯丙基-17-去甲氧基格尔德霉素（17-AAG）促进 CHIP 功能，也可防止体外和体内的 p53 积累和心肌细胞凋亡。CHIP 介导的 p53 降解至少是 17-AAG 的一种心脏保护作用。
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。减少 p53 的含量可防止心肌细胞凋亡，并改善心肌梗死后的心室重构。我们得出结论，抗 p53 方法可能有效治疗心肌梗死。
