Overexpression of uncoupling protein 2 inhibits the high glucose-induced apoptosis of human umbilical vein endothelial cells

Abstract

Ectopic apoptosis of vascular cells plays a critical role in the early stage development of diabetic retinopathy (DR). Uncoupling protein 2 (UCP2) is a mitochondrial modulator which protects against endothelial dysfunction. However, the role which UCP2 plays in endothelial apoptosis and its association with DR was unclear. In the present study, we investigated whether UCP2 functioned as an inhibitor of DR in endothelial cells. Firstly, we noted that in UCP2-knockout mice retinal cell death and damage in vivo was similar to that of db/db diabetic mice. Additionally, UCP2 knockdown induced caspase-3 activation and exaggerated high glucose (HG)-induced apoptosis of human umbilical vein endothelial cells (HUVECs). Conversely, adenovirus-mediated UCP2 overexpression inhibited the apoptosis of HUVECs and HG-induced caspase-3 activation. Furthermore, HG treatment resulted in the opening of the permeability transition pore (PTP) and liberation of cytochrome c from mitochondria to the cytosol in HUVECs. Notably, UCP2 overexpression inhibited these processes. Furthermore, adenovirus-mediated UCP2 overexpression led to a significant increase in intracellular nitric oxide (NO) levels and a decrease in reactive oxygen species (ROS) generation in HUVECs. Collectively, these data suggest that UCP2 plays an anti-apoptotic role in endothelial cells. Thus, we suggest that approaches which augment UCP2 expression in vascular endothelial cells aid in preventing the early stage development and progression of DR.

Resveratrol Prevents ROS‐Induced Apoptosis in High Glucose‐Treated Retinal Capillary Endothelial Cells via the Activation of AMPK/Sirt1/PGC‐1α Pathway

“…Brownlee proposed that mitochondrial production of ROS in response to hyperglycemia may be a key initiating step in the pathogenesis of diabetes, including DR [ 8 ]. Other studies have established a close relation between intracellular ROS production and retinal endothelial cell apoptosis [ 9 , 32 , 33 ]. In our BREC system, we confirmed that HG stimulates ROS production leading to cleaved caspase-3 expression and apoptosis.…”

“…A hypothesis has been proposed that high blood glucose induces oxidative stress through the generation of excessive reactive oxygen species (ROS), which play a dominant role in the development of chronic complications caused by diabetes, including retinopathy [ 7 , 8 ]. Several studies suggested that HG can lead to overproduction of ROS in endothelial cells and subsequent apoptosis [ 9 ]. Peroxisome proliferator-activated receptor- γ coactivator 1 α (PGC-1 α ) is an important mediator of the metabolic effects of ROS, where PGC-1 α activation results in the increase of mitochondrial energy metabolism and the cellular capacity to detoxify ROS, thereby reprogramming cell metabolism to maintain survival [ 10 – 13 ].…”

Inhibition of autophagy promoted high glucose/ROS-mediated apoptosis in ADSCs

“…A hypothesis has been proposed that high blood glucose induces oxidative stress through the generation of excessive ROS, which play a dominant role in the development of chronic complications caused by diabetes [ 32 , 33 ]. Several studies have suggested that high glucose can lead to the accumulation of ROS in endothelial cells and initiate apoptosis [ 34 ]. Peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) is an important mediator of the metabolic effects of ROS, as PGC-1α activation results in increases in mitochondrial energy metabolism and the cellular capacity to detoxify ROS, thereby reprogramming cell metabolism to maintain survival [ 35 , 36 ].…”

CTRP9 induces mitochondrial biogenesis and protects high glucose-induced endothelial oxidative damage via AdipoR1 -SIRT1- PGC-1α activation

“…Vascular lesions are the main complications of diabetes and the primary reason for death caused by diabetes [3]. Pathological and physiological changes caused by high glucose such as oxidative stress, activation of sorbitol bypass metabolic abnormalities, and decreased mitochondrial biogenesis, are associated with endothelial dysfunction [4]. Therefore, reducing vessel damage and maintaining endothelial cell function are essential to slow the development of diabetic complications and improve the living quality of diabetes patients.…”