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

Ischemic cardiomyopathy (ICM) is characterized 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 SNEP1 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 directly interacted and deSUMOylates the SUMO2-mediated modification of MEF2C at lysine 407, consequently promoting the protein stability and phase separation of MEF2C. 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 unrecognized 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. We conducted RNA-sequencing analysis on heart tissues at marginal zone of infarcted area in ICM mice compared with the sham controls.