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Hydrogen Sulfide Protects Against High Glucose-Induced Human Umbilical Vein Endothelial Cell Injury Through Activating PI3K/Akt/eNOS Pathway

Authors Lin F, Yang Y, Wei S, Huang X, Peng Z, Ke X, Zeng Z, Song Y

Received 16 December 2019

Accepted for publication 5 February 2020

Published 14 February 2020 Volume 2020:14 Pages 621—633

DOI https://doi.org/10.2147/DDDT.S242521

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 4

Editor who approved publication: Dr Anastasios Lymperopoulos


Fengxia Lin,1,* Yiying Yang,2,* Shanyin Wei,1 Xiaojing Huang,1 Zhijian Peng,1 Xiao Ke,3 Zhicong Zeng,1 Yinzhi Song1

1Department of Cardiology, Shenzhen Bao’an Traditional Chinese Medicine Hospital Group, The Affiliated Hospital of Guangzhou University of Chinese Medicine, Shenzhen 518133, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, People’s Republic of China; 3Department of Cardiology, Fuwai Hospital, Chinese Academy of Medical Sciences, (Shenzhen Sun Yat-sen Cardiovascular Hospital), Shenzhen 518057, People’s Republic of China

*These authors contributed equally to this work

Correspondence: Zhicong Zeng; Yinzhi Song Email 2436225392@qq.com; songyinzhi@126.com

Purpose: Dysfunction of endothelial cells plays a key role in the pathogenesis of diabetic atherosclerosis. High glucose (HG) has been found as a key factor in the progression of diabetic complications, including atherosclerosis. PI3K/Akt/eNOS signaling pathway has been shown to involve in HG-induced vascular injuries. Hydrogen sulfide (H2S) has been found to exhibit protective effects on HG-induced vascular injuries. Moreover, H2S activates PI3K/Akt/eNOS pathway in endothelial cells. Thus, the present study aimed to determine if H2S exerts protective effects against HG-induced injuries of human umbilical vein endothelial cells (HUVECs) via activating PI3K/Akt/eNOS signaling.
Materials and Methods: The endothelial protective effects of H2S were evaluated and compared to the controlled groups. Cell viability, cell migration and tube formation were determined by in vitro functional assays; protein levels were evaluated by Western blot assay and ELISA; cell apoptosis was determined by Hoechst 33258 nuclear staining; Reactive oxygen species (ROS) production was evaluated by the ROS detection kit.
Results: HG treatment significantly inhibited PI3K/Akt/eNOS signaling in HUVECs, which was partially reversed by the H2S treatment. HG treatment inhibited cell viability of HUVECs, which were markedly prevented by H2S or PI3K agonist Y-P 740. HG treatment also induced HUVEC cell apoptosis by increasing the protein levels of cleaved caspase 3, Bax and Bcl-2, which were significantly attenuated by H2S or 740 Y-P. ROS production and gp91phox protein level were increased by HG treatment in HUVECs and this effect can be blocked by the treatment with H2S or Y-P 740. Moreover, HG treatment increased the protein levels of pro-inflammatory cytokines, caspase-1 and phosphorylated JNK, which was significantly attenuated by H2S or Y-P 740. Importantly, the cytoprotective effect of H2S against HG-induced injury was inhibited by LY294002 (an inhibitor of PI3K/Akt/eNOS signaling pathway).
Conclusion: The present study demonstrated that exogenous H2S protects endothelial cells against HG-induced injuries by activating PI3K/Akt/eNOS pathway. Based on the above findings, we proposed that reduced endogenous H2S levels and the subsequent PI3K/Akt/eNOS signaling impairment may be the important pathophysiological mechanism underlying hyperglycemia-induced vascular injuries.

Keywords: endothelial cells, hydrogen sulfide, high glucose, injury, PI3K/Akt/eNOS


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