Lack of PGC-1α exacerbates high glucose-induced apoptosis in human umbilical vein endothelial cells through activation of VADC1

Endothelial cells (ECs) apoptosis induced by hyperglycemia is intimately involved in the pathophysiology of diabetes and its complication. Although PGC-1 alpha is known for its role in glucose metabolism, its role in ECs injury caused by high glucose milieu is still unclear. Therefore, this study aims to investigate whether PGC-1 alpha participates in ECs apoptosis under high glucose condition. Human umbilical vein endothelial cells (HUVECs) were down-regulated PGC-1 alpha expression by adenovirus-mediated PGC-1 alpha specific siRNA (Ad-shPGC-1 alpha) and exposed to high glucose. Cell viability, apoptosis, mitochondrial membrane permeability, apoptotic marker, reactive oxygen species (ROS), and expression of PGC-1 alpha and VDAC isoforms were studied. Our results showed that high glucose-induced cell apoptosis was associated with an obvious decrease in PGC-1 alpha expression. Lack of PGC-1 alpha exacerbated high glucose-induced cell apoptosis, inner mitochondrial membrane permeabilization, mitochondrial cytochrome c release into cytoplasm and caspases activation; while further decreased cell viability and mitochondrial membrane potential. Analysis of apoptotic markers (Bcl-2, Bax), intracellular ROS and endoplasmic reticulum stress revealed that these mechanisms were not accounted for the effects of Ad-shPGC-1 alpha on apoptosis. However, we found silencing PGC-1 alpha further increased high glucose-induced VDAC1 expression. The pharmacological inhibition of VDAC1 with 4,4'-di-isothiocyanostilbene- 2,2'-disulfonic acid (DIDS) inhibited the increased apoptosis in high glucose-treated PGC-1 alpha knockdown cells. These findings strongly suggest that PGC-1 alpha defect is one of the major mechanisms for ECs apoptosis under high glucose condition, and provide a novel strategy to prevent endothelial dysfunction in diabetes.