Ubiquitin-specific protease 38 exacerbates diabetic cardiomyopathy via post-translational modification of ACAD11.

BACKGROUND

Diabetic cardiomyopathy (DCM) is a prevalent and severe complication of diabetes, for which effective management strategies remain limited. Ubiquitin-specific protease 38 (USP38) has been associated with various cardiovascular diseases. In this study, we investigate the role of USP38 in the pathogenesis of DCM.

METHODS

Cardiomyocyte-specific transgenic and knockout USP38 mice were generated, and diabetic mouse model was established using streptozotocin injections. Neonatal rat cardiomyocytes exposed to high glucose conditions were utilized for in vitro experiments. Cardiac remodeling was assessed through echocardiography, electrophysiological analysis, histological assessment, and molecular analysis.

RESULTS

USP38 expression was significantly upregulated in DCM. Cardiomyocyte-specific USP38 overexpression aggravated cardiac dysfunction, cardiac inflammation and myocardial fibrosis, mitochondrial dysfunction, and increased vulnerability to ventricular arrhythmia in diabetic mice. Conversely, cardiomyocyte-specific USP38 deletion improved cardiac structural and electrical remodeling and attenuated mitochondrial impairment. Similar results were observed in vitro. Mechanistically, RNA-sequencing analysis, immunoprecipitation and mass spectrometry analysis and lipidomic analysis demonstrated that USP38 directly interacts with Acy-CoA dehydrogenase (ACAD11), deubiquitinating and inactivating it. This leads to abnormal fatty acid oxidation and subsequent activation of the receptor for advanced glycation end products (RAGE) pathway in diabetic heart. Pharmacological inhibition of RAGE using FPS-ZM1 hampered cardiac remodeling and dysfunction in cardiomyocyte-specific USP38 overexpressing diabetic mice.

CONCLUSION

The study demonstrates that USP38 exacerbates diabetes-induced cardiac remodeling and DCM via post-translational modification of ACAD11, highlighting a novel therapeutic target for DCM.