Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA.
Nat Rev Cardiol. 2021 Jul;18(7):499-521. doi: 10.1038/s41569-021-00511-w. Epub 2021 Feb 22.
Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell's secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.
心血管疾病（cardiovascular diseases，CVDs），如缺血性心脏病、心肌病、动脉粥样硬化、高血压、中风和心力衰竭，是全球发病率和死亡率的主要原因之一。尽管特定的 CVDs 和相关的心脏代谢异常具有独特的病理生理学和临床表现，但它们通常具有共同的特征，包括内质网（endoplasmic reticulum，ER）中未折叠或错误折叠蛋白质的积累导致的蛋白质稳态破坏。ER 蛋白质稳态由未折叠蛋白反应（unfolded protein response，UPR）调控，这是一种信号通路，可调节细胞的蛋白质折叠能力，以维持细胞的分泌功能。当适应性 UPR 未能维持 ER 内稳态时，会发生适应性或终末 UPR，导致 ER 完整性的破坏和细胞凋亡。ER 应激是一把双刃剑，长期的 ER 应激会导致细胞缺陷，从而扰乱心血管功能。在这篇综述中，我们讨论了 UPR 和 ER 应激反应作为 CVD 的原因和后果的不同作用。我们还总结了我们对 UPR 和 ER 应激在 CVD 发病机制中的重要性的最新理解，并讨论了旨在恢复 CVD 中 ER 蛋白质稳态的潜在治疗策略。
