Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China.
Department of pharmacology, College of Basic Medical Sciences, Binzhou Medical University, Yantai, 264003, China.
Hypertens Res. 2024 May;47(5):1309-1322. doi: 10.1038/s41440-024-01581-2. Epub 2024 Feb 19.
Atrial fibrillation (AF), the most common cardiac arrhythmia, is an important contributor to mortality and morbidity. Ubquitin-specific protease 7 (USP7), one of the most abundant ubiquitin-specific proteases (USP), participated in many cellular events, such as cell proliferation, apoptosis, and tumourigenesis. However, its role in AF remains unknown. Here, the mice were treated with Ang II infusion to induce the AF model. Echocardiography was used to measure the atrial diameter. Electrical stimulation was programmed to measure the induction and duration of AF. The changes in atrial remodeling were measured using routine histologic analysis. Here, a significant increase in USP7 expression was observed in Ang II-stimulated atrial cardiomyocytes and atrial tissues, as well as in atrial tissues from patients with AF. The administration of p22077, the inhibitor of USP7, attenuated Ang II-induced inducibility and duration of AF, atrial dilatation, connexin dysfunction, atrial fibrosis, atrial inflammation, and atrial oxidase stress, and then inhibited the progression of AF. Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-β/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.
心房颤动（AF）是最常见的心律失常，是导致死亡率和发病率的重要因素。泛素特异性蛋白酶 7（USP7）是丰度最高的泛素特异性蛋白酶（USP）之一，参与许多细胞事件，如细胞增殖、凋亡和肿瘤发生。然而，它在 AF 中的作用尚不清楚。在这里，通过给予 Ang II 输注来处理小鼠以诱导 AF 模型。使用超声心动图测量心房直径。进行电刺激以测量 AF 的诱导和持续时间。使用常规组织学分析来测量心房重构的变化。在这里，观察到 Ang II 刺激的心房肌细胞和心房组织以及 AF 患者的心房组织中 USP7 表达显著增加。给予 USP7 的抑制剂 p22077 可减轻 Ang II 诱导的 AF 的可诱导性和持续时间、心房扩张、连接蛋白功能障碍、心房纤维化、心房炎症和心房氧化应激，从而抑制 AF 的进展。从机制上讲，给予 p22077 可减轻 Ang II 诱导的 TGF-β/Smad2、NF-κB/NLRP3、NADPH 氧化酶（NOX2 和 NOX4）信号的激活、CX43、ox-CaMKII、CaMKII、Kir2.1 的上调和 SERCA2a 的下调。总之，这项研究首次表明 USP7 是 AF 的关键驱动因素，并揭示 USP7 可能为心房颤动治疗策略提供新的靶点。
