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

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.

Keywords

DeSUMOylation / ischemic cardiomyopathy / MEF2C / protein phase separation / SENP1

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2025 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.