VBIT-4 attenuates diabetes-associated cardiovascular mitochondrial dysfunction and ROS production in a mouse model of...

Mitochondrial dysfunction and oxidative stress are primary cellular factors in the development of diabetes mellitus and its associated cardiovascular complications. Targeting these processes represents a potential therapeutic strategy. Voltage-dependent anion channels (VDAC) of the mitochondrial outer membrane, which regulate metabolite transport between mitochondria and the cytosol, have emerged as candidate targets for diabetes intervention. In this work, we studied the effect of VBIT-4, an inhibitor of VDAC oligomerization, on the development of mitochondrial dysfunction in cardiovascular cells in a model of diabetes mellitus in vivo and in vitro. The metabolic and cardiac effects of VBIT-4 (10 mg/kg every 48 h for 21 days, intraperitoneally) were assessed in a mouse model of high-fat diet/streptozotocin-induced diabetes. Administration of VBIT-4 was associated with lower blood glucose levels and partial normalization of HR and QT intervals in diabetic animals. Analysis of mitochondrial TEM micrographs and cardiac mitochondrial functional activity indicated that VBIT-4 partially improved State 3 respiration and significantly reduced TBARS production in heart mitochondria of diabetic animals. In cell culture models (primary mouse pulmonary vascular endothelium and HEK293T cells) under hyperlipidemic conditions, both VBIT-4 treatment and silencing of VDAC1 expression significantly reduced DCF and MitoSOX fluorescence, suggesting a potential decrease in mitochondrial reactive oxygen species overproduction. Molecular docking and dynamics simulations predicted that VBIT-4 interacts with the α-helical N-terminus of VDAC1, potentially stabilizing it within the channel pore. Together, these findings suggest that the cardioprotective effects of VBIT-4 in the diabetic setting may involve suppression of VDAC1 oligomerization and associated mitochondrial ROS overproduction.