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

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 β-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 and the E3 ubiquitin ligase Smurf1, thereby suppressing Smurf1-mediated polyubiquitination and proteasomal degradation of SERCA2a. These results reveal a novel protective role of KCNE2 in diabetic hearts and propose KCNE2 upregulation as a potential therapeutic strategy for DCM. Upregulation of KCNE2 ameliorates cardiac dysfunction by reducing Smurf1-mediated SERCA2a polyubiquitination and degradation, and re-establishes SR Ca²⁺ homeostasis in DCM.