Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, 1081 HZ Amsterdam, The Netherlands.
Erasmus Medical Center, Department of Cardiology, 3015 GD Rotterdam, The Netherlands.
Int J Mol Sci. 2021 Jan 5;22(1):442. doi: 10.3390/ijms22010442.
Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia worldwide and is associated with ischemic stroke, heart failure, and substantial morbidity and mortality. Unfortunately, current AF therapy is only moderately effective and does not prevent AF progression from recurrent intermittent episodes (paroxysmal) to persistent and finally permanent AF. It has been recognized that AF persistence is related to the presence of electropathology. Electropathology is defined as structural damage, including degradation of sarcomere structures, in the atrial tissue which, in turn, impairs electrical conduction and subsequently the contractile function of atrial cardiomyocytes. Recent research findings indicate that derailed proteostasis underlies structural damage and, consequently, electrical conduction impairment. A healthy proteostasis is of vital importance for proper function of cells, including cardiomyocytes. Cells respond to a loss of proteostatic control by inducing a heat shock response (HSR), which results in heat shock protein (HSP) expression. Emerging clinical evidence indicates that AF-induced proteostasis derailment is rooted in exhaustion of HSPs. Cardiomyocytes lose defense against structural damage-inducing pathways, which drives progression of AF and induction of HSP expression. In particular, small HSPB1 conserves sarcomere structures by preventing their degradation by proteases, and overexpression of HSPB1 accelerates recovery from structural damage in experimental AF model systems. In this review, we provide an overview of the mechanisms of action of HSPs in preventing AF and discuss the therapeutic potential of HSP-inducing compounds in clinical AF, as well as the potential of HSPs as biomarkers to discriminate between the various stages of AF and recurrence of AF after treatment.
心房颤动（AF）是全球最常见的与年龄相关的心律失常，与缺血性中风、心力衰竭以及大量发病率和死亡率有关。不幸的是，目前的 AF 治疗方法仅能适度有效，并不能防止 AF 从反复发作的间歇性发作（阵发性）进展为持续性，最终发展为永久性 AF。已经认识到 AF 的持续性与电生理学的存在有关。电生理学定义为心房组织中的结构损伤，包括肌节结构的降解，这反过来又损害了电传导，随后损害了心房心肌细胞的收缩功能。最近的研究结果表明，错误的蛋白质稳定是结构损伤和电传导损伤的基础。健康的蛋白质稳定对于细胞，包括心肌细胞的正常功能至关重要。当细胞失去蛋白质稳定控制时，会通过诱导热休克反应（HSR）来做出反应，从而导致热休克蛋白（HSP）的表达。新出现的临床证据表明，AF 诱导的蛋白质稳定失调源于 HSP 的消耗殆尽。心肌细胞失去了抵御结构损伤诱导途径的防御能力，从而导致 AF 的进展和 HSP 的表达诱导。特别是，小分子 HSPB1 通过防止蛋白酶降解肌节结构来保护肌节结构，并且 HSPB1 的过表达可加速实验性 AF 模型系统中结构损伤的恢复。在这篇综述中，我们概述了 HSP 在预防 AF 中的作用机制，并讨论了 HSP 诱导化合物在临床 AF 中的治疗潜力，以及 HSP 作为生物标志物来区分 AF 的各个阶段和治疗后 AF 的复发的潜力。
