Hyperglycemia in patients with diabetes induces vascular endothelial cell apoptosis and subsequent vasculopathy. The aim of the current study was to investigate the pathological mechanism of hyperglycemia-induced endothelial cell apoptosis and vasculopathy using human umbilical vein endothelial cells. As high glucose-induced apoptosis is caused by elevated mitochondrial permeability-mediated release of mitochondrial cytochrome c, the current study examined voltage-dependent anion channel (VDAC1), the controller of mitochondrial permeability, and its regulators, hexokinase2 (HK2), Bcl-2 and Bax. The current study demonstrated that HK2 may be involved in high glucose-induced cell apoptosis, as HK2 overexpression partially reversed high glucose-induced downregulation of mitochondrial/cellular HK2 and Bcl-2 as well as upregulation of mitochondrial Bax. These results suggest that HK2 overexpression partially reversed the reduced binding of HK2 and Bcl-2 and the enhanced binding of Bax to VDAC1, which reduced the high mitochondrial permeability observed under high-glucose conditions. Furthermore, high glucose reduced HK2 transcription via down-regulation of the HK2 transcriptional factor, peroxisome proliferator activated receptor γ (PPARγ). Taken together, these results suggest that PPARγ/HK2 may be novel targets for the prevention of diabetic vasculopathy.
Keywords: Bcl-2; Bcl-2 associated X; hexokinase 2; hyperglycemia; mitochondria; voltage-dependent anion channel 1.