Selenoprotein M protects cardiac endothelial cell integrity against high-glucose stress via enhancing Parkin-mediated mitophagy

Selenoprotein M (SELENOM) has emerged as a crucial factor in maintaining cellular redox homeostasis and mitigating oxidative damage. This study aims to investigate its protective role in cardiac endothelial cells under hyperglycemic stress, a condition commonly associated with diabetes mellitus and its cardiovascular complications. Diabetic mice model and human umbilical vein endothelial cells (HUVECs) were applied for in vivo and in vitro studies. Results reveal that hyperglycemia significantly downregulates SELENOM expression in both diabetic mouse hearts and primary cultured cardiac endothelial cells. Overexpression of SELENOM in HUVECs mitigated high-glucose-induced FITC-Dextran diffusion and the loss of transendothelial electrical resistance. Additionally, SELENOM overexpression decreased reactive oxygen species (ROS) levels, preserved tight junction protein expression, and maintained cellular structural integrity under hyperglycemic conditions. Furthermore, SELENOM overexpression attenuated high-glucose-induced mitochondrial apoptosis. High-glucose conditions decreased Parkin and increased p62 and Beclin1 expressions. SELENOM overexpression restored Parkin levels and promoted co-localization of LAMP1 and TOMM20. Knockdown of Parkin significantly attenuated these protective effects, suggesting the importance of Parkin in Selenoprotein M-mediated mitophagy. Collectively, these findings suggest that Selenoprotein M enhances Parkin-mediated mitophagy to protect endothelial cells from hyperglycemic stress, offering potential therapeutic insights for diabetic cardiovascular complications.