KCNE2 upregulation improves cardiac function by inhibiting Smurf1-mediated SERCA2a degradation in diabetic cardiomyopathy

Diabetic cardiomyopathy (DCM) is associated with impaired calcium handling and downregulation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), though the underlying regulatory mechanisms remain poorly understood. Here, we identify KCNE2, an auxiliary - regulatory subunit of multiple ion channels, as a key regulator of SERCA2a protein stability in the diabetic heart. KCNE2 expression was significantly reduced in high fat diet/streptozotocin-induced diabetic mice and palmitic acid-treated cardiomyocytes. Using LC-MS/MS and co- immunoprecipitation, SERCA2a was identified as a direct binding partner of KCNE2. Knockdown of KCNE2 decreased SERCA2a protein levels without affecting its transcription. Cardiac-specific overexpression of KCNE2 via adenovirus-associated virus 9 delivery restored SERCA2a expression, improved sarcoplasmic reticulum Ca²⁺ cycling, and ameliorated systolic and diastolic dysfunction in diabetic mice. Mechanistically, KCNE2 competitively inhibited the interaction between SERCA2a