High glucose induces apoptosis of HUVECs in a mitochondria‑dependent manner by suppressing hexokinase 2 expression

Abstract

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.

Diabetes Mellitus, Mitochondrial Dysfunction and Ca2+-Dependent Permeability Transition Pore

“…The antidiabetic drugs metformin and rosiglitazone restore the structure of MAM contacts in diabetic animals [ 168 ]. It should be noted that diabetes mellitus is associated with overexpression of VDAC1 in certain tissues (pancreatic β-cells, vascular endothelial cells) [ 169 , 170 , 171 ]. In parallel, an increased amount of Ca 2+ accumulates in mitochondria, which ultimately leads to the activation of apoptosis.…”

“…In parallel, an increased amount of Ca 2+ accumulates in mitochondria, which ultimately leads to the activation of apoptosis. Inhibition of VDAC1 overexpression leads to the suppression of apoptosis in endothelial cells and improves insulin secretion in islets [ 170 , 171 ].…”

Tanshinone IIA alleviates the damage of neurocytes by targeting GLUT1 in ischaemia reperfusion model (in vivo and in vitro experiments)

“…A previous study demonstrated that expression of lactate is increased under oxidative stress along with a reduction of LDHA expression, leading to the consumption of glucose [36], and these processes might be mediated by the MAPK signalling pathway [14]. A recent study also found that overexpression of HK2 might reduce the apoptosis of cells induced by high glucose with a reduction in Bax expression [45]. MDH2 is essential for the conversion of malate to oxaloacetate as part of the proper functioning of the Krebs cycle [7].…”

Physalis alkekengi L. Extract Reduces the Oxidative Stress, Inflammation and Apoptosis in Endothelial Vascular Cells Exposed to Hyperglycemia

“…Growth factors, DNA damage, intracellular Ca 2+ and oxidative stress are the main triggers for the intrinsic pathway [ 69 , 70 ]. They induce upregulation of mitochondrial Bax and the downregulation of hexokinase 2 and Bcl-2 [ 71 ] and determine the cell death. ROS generation in hyperglycemia due to protein glycation, protein kinase C activation or mitochondrial oxidative phosphorylation is closely related to apoptosis and the inhibition of their production under PhyF exposure reduces caspase-3 active form and apoptosis and promotes cell recovery.…”