Xie Ying, Li Qiaoyuan, Bian Xiyun, Yin Yan, Liang Zhuo, Liu Xu, Zhang Tao, Liu Xiaozhi, Quan Xin, Wang Yunlong
Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing, China.
Clin Transl Med. 2025 May;15(5):e70318. doi: 10.1002/ctm2.70318.
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.
缺血性心肌病(ICM)的特征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小鼠模型的心肌细胞和患者中发现了SENP1的下调。SENP1的缺失加剧了体外缺氧诱导的心肌细胞凋亡,并恶化了体内ICM小鼠的心肌细胞损伤。机制上,SENP1使赖氨酸401处SUMO2介导的MEF2C修饰去SUMO化,以稳定蛋白质稳定性。此外,与SENP1的相互作用控制MEF2C的核浓缩,以促进对心肌细胞功能至关重要的基因的表达。当使用9型腺相关病毒挽救SENP1表达时,在ICM小鼠模型中可观察到心肌细胞损伤的减轻。因此,这些发现揭示了SENP1在ICM进展中保护心肌细胞方面以前未被认识的作用和机制,同时为将SENP1开发为ICM诊断和治疗的潜在标志物奠定了基础。要点:在ICM小鼠模型的心肌细胞和患者中,SNEP1下调。SENP1使赖氨酸401处SUMO2介导的MEF2C修饰去SUMO化以实现蛋白质稳定性。与SENP1的相互作用控制MEF2C的核浓缩以促进心肌细胞功能。通过AAV9对SENP1进行心脏挽救可减轻ICM小鼠模型中的缺血性心脏损伤。