Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucose‑induced injury by inhibiting the necroptosis pathway

Lin,Jiaqiong; Chen,Meiji; Liu,Donghong; Guo,Ruixian; Lin,Kai; Deng,Haiou; Zhi,Ximei; Zhang,Weijie; Feng,Jianqiang; Wu,Wen

doi:10.3892/ijmm.2017.3330

Exogenous hydrogen sulfide protects human umbilical vein endothelial cells against high glucose‑induced injury by inhibiting the necroptosis pathway

Authors:
- Jiaqiong Lin
- Meiji Chen
- Donghong Liu
- Ruixian Guo
- Kai Lin
- Haiou Deng
- Ximei Zhi
- Weijie Zhang
- Jianqiang Feng
- Wen Wu
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Affiliations: Department of Endocrinology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangdong Geriatrics Institute, Guangzhou, Guangdong 510080, P.R. China, Department of Pediatrics, Huangpu Division of the First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510700, P.R. China, Department of Ultrasound, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou 510080, P.R. China, Department of Physiology, Zhongshan School of Medicine, Sun Yat‑sen University, Guangzhou 510080, P.R. China
Published online on: December 19, 2017 https://doi.org/10.3892/ijmm.2017.3330
Pages: 1477-1486
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hyperglycemia is a key factor in the development of diabetic complications, including the processes of atherosclerosis. Receptor‑interacting protein 3 (RIP3), a mediator of necroptosis, is implicated in atherosclerosis development. Additionally, hydrogen sulfide (H2S) protects the vascular endothelium against hyperglycemia‑induced injury and attenuates atherosclerosis. On the basis of these findings, the present study aimed to confirm the hypothesis that necroptosis mediates high glucose (HG)‑induced injury in human umbilical vein endothelial cells (HUVECs), and that the inhibition of necroptosis contributes to the protective effect of exogenous H2S against this injury. The results revealed that exposure of HUVECs to 40 mM HG markedly enhanced the expression level of RIP3, along with multiple injuries, including a decrease in cell viability, an increase in the number of apoptotic cells, an increase in the expression level of cleaved caspase‑3, generation of reactive oxygen species (ROS), as well as dissipation of the mitochondrial membrane potential (MMP). Treatment of the cells with sodium hydrogen sulfide (NaHS; a donor of H2S) prior to exposure to HG significantly attenuated the increased RIP3 expression and the aforementioned injuries by HG. Notably, treatment of cells with necrostatin‑1 (Nec‑1), an inhibitor of necroptosis, prior to exposure to HG ameliorated the HG‑induced injuries, leading to a decrease in ROS generation and a loss of MMP. However, pre‑treatment of the cells with Nec‑1 enhanced the HG‑induced increase in the expression levels of cleaved caspases‑3 and ‑9. By contrast, pre‑treatment with Z‑VAD‑FMK, a pan ‑caspase inhibitor, promoted the increased expression of RIP3 by HG. Taken together, the findings of the present study have demonstrated, to the best of our knowledge for the first time, that exogenous H2S protects HUVECs against HG‑induced injury through inhibiting necroptosis. The present study has also provided novel evidence that there is a negative interaction between necroptosis and apoptosis in the HG‑treated HUVECs.

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