PDF(Pubmed)
Abstract：
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
摘要：
背景：泛素特异性蛋白酶38（USP38），属于USP家族，因其在控制蛋白质降解和多种生物过程中的作用而得到认可。心力衰竭（HF）后的室性心律失常（VA）与心室电重塑密切相关，然而，HF中VAs的具体机制仍未得到充分探索。在这项研究中,我们研究了USP38对压力超负荷诱发的HF中VAs的影响。
方法：心脏特异性USP38基因敲除小鼠，心脏特异性USP38转基因小鼠及其匹配的对照同窝小鼠发生由主动脉束带（AB）手术诱导的HF。在对小鼠进行为期四周的AB手术后，进行了全面调查，包括病理分析和电生理评估，以及分子分析。
结果：我们观察到HF小鼠左心室中USP38表达增加。心电图显示USP38基因敲除缩短了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持续时间（APD）和延长有效不应期（ERP）来降低VA的易感性。此外,USP38敲除增加了心室中离子通道和Cx43的表达。相反,USP38过表达观察到VAs的易感性增加以及心室离子通道和Cx43的表达降低。在体内和体外实验中，USP38敲除抑制TBK1/AKT/CAMKII信号,而USP38过表达激活了该途径。
结论：我们的数据表明USP38通过TBK1/AKT/CAMKII信号通路增加HF后对VAs的易感性，因此,USP38可能成为治疗HF后VA的有希望的治疗靶标。
方法：心脏特异性USP38基因敲除小鼠，心脏特异性USP38转基因小鼠及其匹配的对照同窝小鼠发生由主动脉束带（AB）手术诱导的HF。在对小鼠进行为期四周的AB手术后，进行了全面调查，包括病理分析和电生理评估，以及分子分析。
结果：我们观察到HF小鼠左心室中USP38表达增加。心电图显示USP38基因敲除缩短了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持续时间（APD）和延长有效不应期（ERP）来降低VA的易感性。此外,USP38敲除增加了心室中离子通道和Cx43的表达。相反,USP38过表达观察到VAs的易感性增加以及心室离子通道和Cx43的表达降低。在体内和体外实验中，USP38敲除抑制TBK1/AKT/CAMKII信号,而USP38过表达激活了该途径。
结论：我们的数据表明USP38通过TBK1/AKT/CAMKII信号通路增加HF后对VAs的易感性，因此,USP38可能成为治疗HF后VA的有希望的治疗靶标。
