Critical effect of VEGF in the process of endothelial cell apoptosis induced by high glucose.
The underlying molecular mechanism whereby hyperglycemia causes endothelial cell apoptosis is not well understood. This study aims to elucidate the role of survival factor VEGF involved in the apoptosis of endothelial cells induced by elevated glucose. The present study confirmed that high concentration of glucose (25 mmol/l) significantly increased the apoptotic cell number in cultured primary human umbilical vein endothelial cells (HUVEC). Up-regulation of Bax/Bcl-2 ratio and activation of caspase-3 induced by high glucose suggested that mitochondria apoptosis pathway was involved. High glucose significantly reduced VEGF expression in HUVEC both at mRNA and protein levels. p42/44 MAPK phosphorylation was transitory attenuated when exposed to high glucose and preceded VEGF reduction, thus suggesting down-regulation of VEGF through inhibition of p42/44 MAPK. Addition of VEGF prevented HUVEC apoptosis from high glucose exposure. Moreover, elevated reactive oxygen species (ROS) generation, calcium overload, Bax/Bcl-2 ratio, caspase-3 activation in HUVEC induced by high glucose were reversed by pre-challenge with VEGF. This may represent a mechanism for the anti-apoptotic effect of VEGF. These results suggest that down-regulation of VEGF plays a critical role in apoptosis of endothelial cells induced by high glucose and restoration of VEGF might have benefits in the early stage of diabetic endothelial dysfunction.
Yang
Zhonghan
Z
Department of Biochemistry, Zhongshan Medical School, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou 510080, China.
Mo
Xuehua
X
Gong
Qing
Q
Pan
Qiuhui
Q
Yang
Xia
X
Cai
Weibin
W
Li
Chaoyang
C
Ma
Jian-Xing
JX
He
Yunshao
Y
Gao
Guoquan
G
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D017382:Reactive Oxygen Species; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
D017382:Reactive Oxygen Species; D042461:Vascular Endothelial Growth Factor A; D006861:Hydrogen Peroxide; D005947:Glucose; D002118:Calcium