首页> 外文期刊>American Journal of Physiology >CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice.
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CHIP, a cochaperone/ubiquitin ligase that regulates protein quality control, is required for maximal cardioprotection after myocardial infarction in mice.

机译:CHIP是一种调节蛋白质质量控​​制的伴侣蛋白/泛素连接酶,是小鼠心肌梗死后最大程度的心脏保护所必需的。

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Limitation of damage after ischemia and reperfusion injury to the myocardium remains an elusive clinical goal. Previous studies have suggested that molecular chaperones, which include members of the heat shock protein (Hsp) family, may have cardioprotective effects, although the protective role of endogenous chaperones has not been well documented. CHIP (carboxyl terminus of Hsp70-interacting protein) is a cochaperone/ubiquitin ligase that integrates the response to stress at multiple levels. We tested the response of CHIP(-/-) mice to in vivo ischemia and reperfusion injury induced by left anterior descending coronary artery ligation. Compared with wild-type littermates, CHIP(-/-) mice had decreased survival and increased incidence of arrhythmias during reperfusion. The size of myocardial infarction, as assessed by the ratio of infarct area to area at risk, was 50% greater in CHIP(-/-) mice. Increased infarct size was accompanied by impaired upregulation of the chaperone Hsp70 after ischemia-reperfusion injury. In situ analysis also indicated that hearts of CHIP(-/-) mice were more prone to develop apoptosis in cardiomyocytes and especially endothelial cells of intramural vessels. Previous studies have found that CHIP plays a central role in maintaining protein quality control and coordinating the response to stress. The present data indicate that these functions of CHIP provide a critical cardioprotective effect in the setting of ischemia-reperfusion injury due in part to increased apoptosis in cardiac cells. Quality control mechanisms therefore may be underappreciated clinical targets for maximizing myocardial protection after injury.
机译:限制缺血和再灌注损伤后对心肌的损害仍然是难以实现的临床目标。先前的研究表明,分子伴侣,包括热休克蛋白(Hsp)家族的成员,可能具有心脏保护作用,尽管尚未充分证明内源性伴侣的保护作用。 CHIP(与Hsp70相互作用的蛋白的羧基末端)是一种伴侣蛋白/泛素连接酶,可在多个水平上整合对应激的反应。我们测试了CHIP(-/-)小鼠对体内缺血和左前降支冠状动脉结扎诱导的再灌注损伤的反应。与野生型同窝仔相比,CHIP(-/-)小鼠在再灌注期间存活率降低,心律不齐的发生率增加。通过梗塞面积与风险面积之比评估,在CHIP(-/-)小鼠中,心肌梗塞的大小增加了50%。缺血-再灌注损伤后,梗塞面积增加,伴有伴侣蛋白Hsp70上调受损。原位分析还表明,CHIP(-/-)小鼠的心脏更倾向于在心肌细胞特别是壁内血管的内皮细胞中发生凋亡。先前的研究发现,CHIP在维持蛋白质质量控​​制和协调对压力的反应中起着核心作用。目前的数据表明,CHIP的这些功能在局部缺血/再灌注损伤中提供了关键的心脏保护作用,这部分是由于心脏细胞凋亡增加所致。因此,为了使损伤后的心肌得到最大程度的保护,质量控制机制可能未得到充分重视。

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