Department of Cardiology, Renmin Hospital of Wuhan University, 238 Jiefang Road, Wuhan, 430060, Hubei, China.
Hubei Key Laboratory of Cardiology, Wuhan, China.
Mol Med. 2024 Jun 27;30(1):97. doi: 10.1186/s10020-024-00846-3.
Ubiquitin-specific protease 38 (USP38), belonging to the USP family, is recognized for its role in controlling protein degradation and diverse biological processes. Ventricular arrhythmias (VAs) following heart failure (HF) are closely linked to ventricular electrical remodeling, yet the specific mechanisms underlying VAs in HF remain inadequately explored. In this study, we examined the impact of USP38 on VAs in pressure overload-induced HF.
Cardiac-specific USP38 knockout mice, cardiac-specific USP38 transgenic mice and their matched control littermates developed HF induced by aortic banding (AB) surgery. After subjecting the mice to AB surgery for a duration of four weeks, comprehensive investigations were conducted, including pathological analysis and electrophysiological assessments, along with molecular analyses.
We observed increased USP38 expression in the left ventricle of mice with HF. Electrocardiogram showed that the USP38 knockout shortened the QRS interval and QTc, while USP38 overexpression prolonged these parameters. USP38 knockout decreased the susceptibility of VAs by shortening action potential duration (APD) and prolonging effective refractory period (ERP). In addition, USP38 knockout increased ion channel and Cx43 expression in ventricle. On the contrary, the increased susceptibility of VAs and the decreased expression of ventricular ion channels and Cx43 were observed with USP38 overexpression. In both in vivo and in vitro experiments, USP38 knockout inhibited TBK1/AKT/CAMKII signaling, whereas USP38 overexpression activated this pathway.
Our data indicates that USP38 increases susceptibility to VAs after HF through TBK1/AKT/CAMKII signaling pathway, Consequently, USP38 may emerge as a promising therapeutic target for managing VAs following HF.
泛素特异性蛋白酶 38（USP38）属于 USP 家族，其作用是控制蛋白降解和多种生物过程。心力衰竭（HF）后发生的室性心律失常（VA）与心室电重构密切相关，但 HF 中 VA 的具体机制仍未得到充分探讨。在这项研究中，我们研究了 USP38 对压力超负荷诱导的 HF 中 VA 的影响。
心脏特异性 USP38 敲除小鼠、心脏特异性 USP38 转基因小鼠及其匹配的对照同窝仔鼠接受主动脉缩窄（AB）手术诱导 HF。在 AB 手术后 4 周，对小鼠进行综合研究，包括病理分析和电生理评估，以及分子分析。
我们观察到 HF 小鼠左心室 USP38 表达增加。心电图显示 USP38 敲除缩短了 QRS 间期和 QTc，而 USP38 过表达延长了这些参数。USP38 敲除通过缩短动作电位时程（APD）和延长有效不应期（ERP）降低了 VA 的易感性。此外，USP38 敲除增加了心室离子通道和 Cx43 的表达。相反，USP38 过表达增加了 VA 的易感性，降低了心室离子通道和 Cx43 的表达。在体内和体外实验中，USP38 敲除抑制了 TBK1/AKT/CAMKII 信号通路，而 USP38 过表达激活了该通路。
我们的数据表明，USP38 通过 TBK1/AKT/CAMKII 信号通路增加 HF 后 VA 的易感性，因此，USP38 可能成为 HF 后 VA 管理的有前途的治疗靶点。
