在心脏缩期间,ATF6可以防止蛋白质错误折叠
Christoph Hofmann1, Marjan Aghajani2, Cecily D Alcock2
1Department of Internal Medicine III (Cardiology, Angiology, and Pneumology), Heidelberg University Hospital, Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany; SDSU Heart Institute and Department of Biology, San Diego State University, San Diego, CA, USA.
Journal of molecular and cellular cardiology
|February 24, 2024
概括
展开的蛋白质反应 (UPR) 转录因子ATF6保护心脏在缩期间. 缺少ATF6导致蛋白质错折和心力衰竭,突出其在维持心脏功能的关键适应性作用.
科学领域:
- 心脏病学 心脏病学
- 分子生物学分子生物学
- 细胞应激反应的应激反应
背景情况:
- 心肌细胞在压力过载时激活未折叠蛋白质反应 (UPR).
- 据信,UPR可以增强内细胞网膜蛋白质折叠能力,并维持蛋白质稳定.
- 在压力过载期间的ATF6缺乏与心力衰竭相关,这表明ATF6通过预防蛋白质错折对心肌功能障碍起着保护作用.
研究的目的:
- 调查ATF6在预防病理性心脏缩期间有毒蛋白质误折的作用.
- 为了确定ATF6激活是否是心脏缩的常见反应.
- 评估ATF6缺乏对蛋白质折叠和心肌功能在过度缩压力下的影响.
主要方法:
- 在小鼠中诱导病态心脏缩,使用慢性异二醇输液和横向大动脉收缩 (TAC).
- 对UPR激活的评估,包括ATF6及其目标基因.
- 在野生类型 (WT) 和ATF6淘汰赛 (KO) 老鼠的过度缩心脏中,对多基化蛋白和可溶性粉胺寡合体进行量化.
- 在WT和ATF6KO小鼠中评估心肌功能.
主要成果:
- 包括ATF6在内的UPR的激活是小鼠对病理性心脏缩的常见反应.
- 在ATF6KO小鼠中,UPR目标基因的诱导不足,导致心脏生长受损.
- 在TAC后的ATF6KO心脏中,与WT心脏相比,错误折叠的蛋白质 (多基化蛋白和粉样蛋白寡合体) 积累的水平显著更高.
- 在ATF6KO小鼠中,蛋白质错折的增加与心肌功能受损有关.
结论:
- ATF6通过保护心肌细胞免受蛋白质错误折叠,在心脏缩中发挥关键的适应性作用.
- UPR转录因子ATF6对于维持蛋白质静止和预防高变压下心脏功能障碍至关重要.
- 准ATF6或UPR通路可能为管理与心脏缩相关的心力衰竭提供治疗策略.
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