Downregulation of VEGF and upregulation of TL1A expression induce HUVEC apoptosis in response to high glucose stimuli

Yu,Miao; Lu,Guihua; Zhu,Xun; Huang,Zhibin; Feng,Chong; Fang,Rong; Wang,Yesong; Gao,Xiuren

doi:10.3892/mmr.2016.4924

Downregulation of VEGF and upregulation of TL1A expression induce HUVEC apoptosis in response to high glucose stimuli

Authors:
- Miao Yu
- Guihua Lu
- Xun Zhu
- Zhibin Huang
- Chong Feng
- Rong Fang
- Yesong Wang
- Xiuren Gao
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Affiliations: Department of Cardiology, First Affiliated Hospital of Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China, Department of Microbiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China, Key Laboratory of Assisted Circulation, Ministry of Health, Guangzhou, Guangdong 710068, P.R. China
Published online on: February 22, 2016 https://doi.org/10.3892/mmr.2016.4924
Pages: 3265-3272

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Abstract

High glucose‑induced endothelial cell apoptosis is considered to be the initiator of diabetes‑associated vascular complications. Experiments in vivo and in vitro have demonstrated that high glucose levels contribute to the apoptosis of endothelial cells by mediating cellular dysfunction and metabolic disorder via the production of various cytokines. As the most important endogenous vascular regulators, the balance between pro‑proliferative effector vascular endothelial growth factor (VEGF) and anti‑proliferative effector tumor necrosis factor‑like cytokine 1A (TL1A) is important in the modulation of endothelial cell survival and proliferation, and neovascularization. The present study aimed to explore whether the imbalance between VEGF and TL1A affected the apoptosis of human umbilical vein endothelial cells (HUVECs) exposed to high glucose conditions and then further investigated the potential mechanism. The results showed that the downregulation of VEGF in combination with the upregulation of TL1A in response to high glucose levels led to enhanced HUVEC apoptosis. Further experiments revealed that silencing high glucose‑induced TL1A expression using TL1A small interfering (si)RNA or the overexpression of VEGF by transfection with VEGF DNA resulted in a reduced HUVEC apoptosis rate compared with the controls. The effects occurred by attenuating and activating the phosphoinositide 3‑kinase/Akt/endothelial nitric oxide synthase pathway, respectively. In addition, VEGF and TL1A inhibited each other in hyperglycemia. In conclusion, these findings provide theoretical support for the further investigation of novel therapeutic strategies designed to maintain the balance between VEGF and TL1A and, thus, to prevent the onset and progression of endothelial cell apoptosis in response to high glucose stimuli.

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