Atrial fibrillation (AF) is the most common human arrhythmia in clinical practice and may be promoted by atrial inflammation and fibrosis. Ubiquitination is an important posttranslational modification process that is reversed by deubiquitinating enzymes (DUBs). DUBs play critical roles in modulating the degradation, activity, trafficking, and recycling of substrates. However, less research has focused on the role of DUBs in AF. Here, we investigated the effect of ubiquitin C-terminal hydrolase 1 (UCHL1), an important DUB, on the development of AF induced by angiotensin II (Ang II). Male wild-type mice were treated with the UCHL1 inhibitor LDN57444 (LDN) at a dose of 40 μg/kg and infused with Ang II (2000 ng/kg/min) for 3 weeks. Our results showed that Ang II-infused wild-type (WT) mice had higher systolic blood pressure and an increased incidence and duration of AF. Conversely, this effect was attenuated in LDN-treated mice. Moreover, the administration of LDN significantly reduced Ang II-induced left atrial dilation, fibrosis, inflammatory cell infiltration, and reactive oxygen species (ROS) production. Mechanistically, LDN treatment inhibited the activation of multiple signaling pathways (the AKT, ERK1/2, HIF-1α, and TGF-β/smad2/3 pathways) and the expression of CX43 protein in atrial tissues compared with that in vehicle-treated control mice. Overall, our study identified UCHL1 as a novel regulator that contributes to Ang II-induced AF and suggests that the administration of LDN may represent a potential therapeutic approach for treating hypertensive AF.

中文翻译：

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LDN-57444 对 UCHL1 的抑制减弱了 Ang II 诱导的小鼠心房颤动

心房颤动 (AF) 是临床实践中最常见的人类心律失常，可能由心房炎症和纤维化促进。泛素化是一个重要的翻译后修饰过程，可被去泛素化酶 (DUB) 逆转。DUB 在调节底物的降解、活性、运输和回收方面发挥着关键作用。然而，很少有研究关注 DUB 在 AF 中的作用。在这里，我们研究了重要的 DUB 泛素 C 末端水解酶 1 (UCHL1) 对血管紧张素 II (Ang II) 诱导的 AF 发展的影响。雄性野生型小鼠用 UCHL1 抑制剂 LDN57444 (LDN) 治疗，剂量为 40 μg/kg，并输注 Ang II (2000 ng/kg/min) 3 周。我们的研究结果表明，注入 Ang II 的野生型 (WT) 小鼠收缩压较高，AF 的发生率和持续时间增加。相反，这种效应在 LDN 治疗的小鼠中减弱。此外，LDN 的施用显着降低了 Ang II 诱导的左心房扩张、纤维化、炎性细胞浸润和活性氧 (ROS) 的产生。从机制上讲，与载体处理的对照相比，LDN 处理抑制了多种信号通路（AKT、ERK1/2、HIF-1α 和 TGF-β/smad2/3 通路）的激活和心房组织中 CX43 蛋白的表达老鼠。总体而言，我们的研究确定 UCHL1 是一种新的调节因子，有助于 Ang II 诱导的 AF，并表明 LDN 的给药可能代表治疗高血压 AF 的潜在治疗方法。