Zhong Xin, Xu Jianjiang, Shi Xiaowen, Lyu Yiting, Qian Yuanyuan, Fang Zimin, Wang Zixuan, Xing Jincheng, Ye Bozhi, Xu Jiajun, Han Jibo
Department of Cardiology, The Second Affiliated Hospital of Jiaxing University, Zhejiang, China (X.Z., Jianjiang Xu, X.S., Y.L., Jiajun Xu, J.H.).
Zhejiang Key Laboratory of Blood-Stasis-Toxin Syndrome, Zhejiang Chinese Medical University, Hangzhou, China (Y.Q.).
Hypertension. 2025 Apr;82(4):704-715. doi: 10.1161/HYPERTENSIONAHA.124.23823. Epub 2025 Feb 5.
Cardiac hypertrophy constitutes the primary pathological basis for heart failure and exerts a considerable influence on morbidity and mortality. Deubiquitinating enzymes are crucial regulators of protein degradation and play a pivotal role in cardiac pathophysiology. This study aimed to clarify the involvement of a deubiquitinating enzyme, MYSM1 (Myb-like, SWIRM [Swi3p, Rsc8p and Moira], and MPN [Mpr1/Pad1 N-terminal] domains 1), in cardiac hypertrophy and to explore the underlying mechanism.
Cardiac hypertrophy was developed by angiotensin II or transverse aortic constriction surgery. Cardiomyocyte-specific knockdown of MYSM1 was accomplished using the adeno-associated virus serotype 9--shRNA. Co-immunoprecipitation combined with liquid chromatography-tandem mass spectrometry analysis was utilized to identify potential substrates of MYSM1.
First, we discovered that the expression of MYSM1 increases during cardiac hypertrophy. MYSM1 knockdown mitigated cardiac dysfunction and hypertrophy after angiotensin II administration. Cardiomyocyte-specific knockdown of MYSM1 with adeno-associated virus serotype 9 alleviated myocardial dysfunction and hypertrophy caused by transverse aortic constriction surgery. Through co-immunoprecipitation and LC-MS, poly (ADP-ribose) polymerase 1 (PARP1) was identified as a potential substrate protein of MYSM1. PARP1 initiates a novel form of programmed cell death termed parthanatos, which is characterized by excessive PARylation, nuclear translocation of AIF, and depletion of nicotinamide adenine dinucleotide. MYSM1 deubiquitinates and stabilizes PARP1 in an MPN domain-dependent manner. In addition, MYSM1 mediates cardiac hypertrophy through PARP1-dependent cardiomyocyte parthanatos.
This study identified the role of the MYSM1-PARP1 axis in mediating cardiac hypertrophy and suggested that MYSM1 is a promising pharmacological target for the treatment of cardiac hypertrophy.
心脏肥大是心力衰竭的主要病理基础，对发病率和死亡率有重大影响。去泛素化酶是蛋白质降解的关键调节因子，在心脏病理生理学中起关键作用。本研究旨在阐明去泛素化酶MYSM1（Myb样、SWIRM[Swi3p、Rsc8p和Moira]和MPN[Mpr1/Pad1 N端]结构域1）在心脏肥大中的作用，并探讨其潜在机制。
通过血管紧张素II或主动脉缩窄手术诱导心脏肥大。使用腺相关病毒9型-shRNA实现心肌细胞特异性敲低MYSM1。采用免疫共沉淀结合液相色谱-串联质谱分析来鉴定MYSM1的潜在底物。
首先，我们发现心脏肥大过程中MYSM1的表达增加。敲低MYSM1可减轻血管紧张素II给药后的心脏功能障碍和肥大。用腺相关病毒9型进行心肌细胞特异性敲低MYSM1可减轻主动脉缩窄手术引起的心肌功能障碍和肥大。通过免疫共沉淀和液相色谱-质谱联用分析，聚（ADP-核糖）聚合酶1（PARP1）被鉴定为MYSM1的潜在底物蛋白。PARP1启动一种称为parthanatos的新型程序性细胞死亡形式，其特征是过度的PAR化、凋亡诱导因子的核转位以及烟酰胺腺嘌呤二核苷酸的消耗。MYSM1以MPN结构域依赖的方式使PARP1去泛素化并使其稳定。此外，MYSM1通过PARP1依赖的心肌细胞parthanatos介导心脏肥大。
本研究确定了MYSM1-PARP1轴在介导心脏肥大中的作用，并表明MYSM1是治疗心脏肥大的一个有前景的药理学靶点。
