非正规形式的ERAD调节心脏缩
Erik A Blackwood1, Lauren F MacDonnell1, Donna J Thuerauf2
1Translational Cardiovascular Research Center and Department of Internal Medicine, University of Arizona College of Medicine-Phoenix (E.A.B., L.F.M., A.S.B., V.B.M., C.C.G.).
Circulation
|November 1, 2022
概括
通过增强SGK1的ER相关降解,瓦洛辛含蛋白相互作用膜蛋白 (VIMP) 的降解改善了心脏缩. 这项研究揭示了ERAD-Out作为一种影响心脏应激反应的新机制.
科学领域:
- 分子生物学
- 心血管研究
- 细胞应激反应
背景情况:
- 由于错误折叠的蛋白质,心脏缩会增加内质网膜 (ER) 的压力.
- 与ER相关的降解 (ERAD) 消除了错误折叠的蛋白质,但其在心脏缩中的in vivo作用和速率尚未研究.
- 含有瓦洛辛的蛋白相互作用膜蛋白 (VIMP) 是ERAD的一个关键启动剂.
研究的目的:
- 在体内研究ERAD在病态心脏缩中的作用和速率.
- 检查VIMP在压力过载引起的心脏缩中的功能.
- 阐明ERAD影响心脏缩的机制.
主要方法:
- 开发了一种使用心肌细胞特异性腺相关病毒血清9的新方法来测量体内ERAD流量.
- 使用腺相关病毒血清9来调节小鼠心中的VIMP表达 (敲击或过度表达).
- 在小鼠中通过横向大动脉收缩诱导心脏缩.
主要成果:
- 在人类心力衰竭和压力过度诱导的心脏缩的小鼠中,ERAD流量有所减少.
- VIMP的降低意外地增加了ERAD并改善了心脏缩,而VIMP的过度表达则使其恶化.
- 通过一种新的ERAD-Out途径降低了SGK1水平,这是心脏缩的关键驱动因素.
结论:
- 在心肌细胞中SGK1降解中,ERAD-Out是一种新发现的非正规的ERAD通路.
- 通过抑制ERAD-Out和SGK1降解,VIMP在病态心脏缩中起着有害的作用.
- 针对ERAD-Out是一种潜在的治疗策略,用于治疗心脏缩和心力衰竭.
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