DACH1 SUMOylation protects against diabetic cardiomyopathy by suppressing endoplasmic reticulum stress.

INTRODUCTION Endoplasmic reticulum (ER) stress is a key driver of diabetic cardiomyopathy (DCM), but its upstream regulators are incompletely defined. The transcription factor DACH1 is genetically linked to diabetes and cardiovascular risk, yet its role in the diabetic heart is unknown.

Objectives

This study aimed to elucidate the function and post-translational regulation of DACH1 in DCM, focusing on its interplay with ER stress.

Methods

Cardiac function, ER stress, and apoptosis were assessed in db/db mice and high glucose-treated cardiomyocytes. AAV9 was used for cardiac-specific DACH1 overexpression in vivo. SUMOylation and ubiquitination of DACH1 were analyzed via co-immunoprecipitation, mutagenesis, and proteasome inhibition assays.

Results

Myocardial DACH1 protein, but not its mRNA, was significantly reduced in experimental DCM. Restoring cardiac DACH1 alleviated dysfunction, ER stress, apoptosis, and fibrosis in diabetic mice. DACH1 stability was associated with SUMOylation at lysines K348, K599, and K631, and TRIM28 facilitated this modification in our experimental system. This modification was reduced under diabetic conditions and was associated with increased ubiquitin-proteasome degradation of DACH1. Enhancing SUMO1 increased DACH1 stability, helped preserve DACH1 nuclear retention, and protected cardiomyocytes from high glucose-induced ER stress and apoptosis.

Conclusion

Impaired SUMOylation may contribute to DACH1 depletion in the diabetic heart. SUMOylation-dependent stabilization of DACH1 represents a potential cardioprotective pathway that mitigates diabetic myocardial injury by suppressing ER stress.