Downregulation of SENP1 impairs nuclear condensation of MEF2C and deteriorates ischemic cardiomyopathy

IF 7.9 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Clinical and Translational Medicine Pub Date : 2025-05-07 DOI:10.1002/ctm2.70318

Ying Xie, Qiaoyuan Li, Xiyun Bian, Yan Yin, Zhuo Liang, Xu Liu, Tao Zhang, Xiaozhi Liu, Xin Quan, Yunlong Wang

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Abstract

Ischemic cardiomyopathy (ICM) is characterised by the insufficient capacity of the heart to effectively pump blood, which ultimately contributes to heart failure (HF). In this study, the down regulation of SENP1 is identified in the cardiomyocyte of ICM mouse models and in patients. The depletion of SENP1 exacerbates hypoxia-induced apoptosis of cardiomyocytes in vitro and deteriorated cardiomyocyte injury of ICM mice in vivo. Mechanistically, SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for stabilising protein stability. Moreover, the interaction with SENP1 controls the nuclear condensation of MEF2C to promote the expression of genes critical for cardiomyocyte function. When rescuing SENP1 expression using adeno-associated virus serotype 9, the attenuation of cardiomyocyte injury is discerned in the mouse model of ICM. Therefore, these finding elicits a previously unrecognised role and mechanism of SENP1 in safeguarding cardiomyocyte in ICM progression while establishing a basis for the development of SENP1 as a potential marker for ICM diagnosis and treatment.

Key points

SNEP1 is downregulated in the cardiomyocyte of ICM mouse models and in patients.
SENP1 deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 401 for protein stability.
The interaction with SENP1 controls the nuclear condensation of MEF2C to promote cardiomyocyte function.
Cardiac rescue of SENP1 alleviates ischemic heart injury in ICM mouse models by AAV9.

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SENP1的下调会损害MEF2C的核凝聚并恶化缺血性心肌病

缺血性心肌病（ICM）的特点是心脏有效泵血能力不足，最终导致心力衰竭（HF）。在本研究中，在ICM小鼠模型和患者的心肌细胞中发现了SENP1的下调。SENP1的缺失在体外加剧了缺氧诱导的心肌细胞凋亡，并在体内恶化了ICM小鼠的心肌细胞损伤。在机制上，SENP1使sumo2介导的MEF2C赖氨酸401位点的修饰脱苏酰基化，以稳定蛋白质的稳定性。此外，与SENP1的相互作用控制MEF2C的核凝聚，促进心肌细胞功能关键基因的表达。当使用腺相关病毒血清型9挽救SENP1表达时，在小鼠ICM模型中发现心肌细胞损伤的衰减。因此，这些发现引发了SENP1在ICM进展中保护心肌细胞的先前未被认识的作用和机制，同时为SENP1作为ICM诊断和治疗的潜在标志物的发展奠定了基础。在ICM小鼠模型和患者心肌细胞中，SNEP1表达下调。SENP1使sumo2介导的MEF2C赖氨酸401位点的修饰脱苏酰基化，以保持蛋白质的稳定性。与SENP1的相互作用控制MEF2C的核凝聚，从而促进心肌细胞功能。心脏救援SENP1通过AAV9减轻ICM小鼠模型缺血性心脏损伤。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical and Translational Medicine Multiple-

CiteScore

15.90

自引率

1.90%

发文量

450

审稿时长

4 weeks

期刊介绍： Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.