Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice
Enhancement of proteasomal function protects against cardiac proteinopathy and ischemia/reperfusion injury in mice
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DOI：
10.1172/jci45709
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发表时间：
2011-09-01
影响因子：
15.9
通讯作者：
Wang, Xuejun
中科院分区：
文献类型：
--
作者：
Li, Jie;Horak, Kathleen M.;Wang, Xuejun
泛素-蛋白酶体系统降解大多数细胞内蛋白，包括错误折叠的蛋白。proteins.蛋白酶体功能不全（PFI）在蛋白质病如结蛋白相关性心肌病中已被观察到，并与许多常见疾病如扩张型心肌病和缺血性心脏病有关。然而，PFI的致病作用尚未确定。在这里，我们创建了诱导型Tg小鼠与心肌细胞限制性过表达蛋白酶体28亚基α（CR-PA 28 α OE），以研究是否上调11 S蛋白酶体增强蛋白酶体在小鼠中的蛋白水解功能，如果是这样的话，增强是否可以拯救真正的蛋白质病，并防止缺血/再灌注（I/R）损伤。我们发现CR-PA 28 alpha OE并没有改变正常蛋白质和心脏功能的稳态，但确实促进了心脏中替代错误折叠蛋白质的降解。通过用CR-PA 28 α OE小鼠与代表结蛋白相关心肌病的成熟模型的小鼠交配，我们证明CR-PA 28 α OE显著降低异常蛋白聚集。心脏肥大减少，动物的寿命增加。此外，PA 28 α敲低促进，而PA 28 α过表达减弱，与结蛋白相关的心肌病在培养的心肌细胞中的突变蛋白的积累。此外，CR-PA 28 α OE限制了心肌I/R损伤小鼠的梗死面积，并预防了再灌注后心功能障碍。因此，我们得出结论，心脏蛋白酶体蛋白水解功能的良性增强可以通过CR-PA 28 α OE实现，PFI在心脏蛋白病和心肌I/R损伤中起主要致病作用。
The ubiquitin-proteasome system degrades most intracellular proteins, including misfolded. proteins. Proteasome functional insufficiency (PFI) has been observed in proteinopathies, such as desmin-related cardiomyopathy, and implicated in many common diseases, including dilated cardiomyopathy and ischemic heart disease. However, the pathogenic role of PFI has not been established. Here we created inducible Tg mice with cardiomyocyte-restricted overexpression of proteasome 28 subunit alpha (CR-PA28 alpha OE) to investigate whether upregulation of the 11S proteasome enhances the proteolytic function of the proteasome in mice and, if so, whether the enhancement can rescue a bona fide proteinopathy and protect against ischemia/reperfusion (I/R) injury. We found that CR-PA28 alpha OE did not alter the homeostasis of normal proteins and cardiac function, but did facilitate the degradation of a surrogate misfolded protein in the heart. By breeding mice with CR-PA28 alpha OE with mice representing a well-established model of desmin-related cardiomyopathy, we demonstrated that CR-PA28 alpha OE markedly reduced aberrant protein aggregation. Cardiac hypertrophy was decreased, and the lifespan of the animals was increased. Furthermore, PA28 alpha knockdown promoted, whereas PA28 alpha overexpression attenuated, accumulation of the mutant protein associated with desmin-related cardiomyopathy in cultured cardiomyocytes. Moreover, CR-PA28 alpha OE limited infarct size and prevented postreperfusion cardiac dysfunction in mice with myocardial I/R injury. We therefore conclude that benign enhancement of cardiac proteasome proteolytic function can be achieved by CR-PA28 alpha OE and that PFI plays a major pathogenic role in cardiac proteinopathy and myocardial I/R injury.