Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction

Chen,Shuhua; Yang,Jie; Xiang,Hong; Chen,Wei; Zhong,Hua; Yang,Guoping; Fang,Ting; Deng,Hao; Yuan,Hong; Chen,Alex  F.; Lu,Hongwei

doi:10.3892/ijmm.2015.2100

April-2015 Volume 35 Issue 4

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April-2015 Volume 35 Issue 4

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Article

Role of sphingosine-1-phosphate receptor 1 and sphingosine-1-phosphate receptor 2 in hyperglycemia-induced endothelial cell dysfunction

Authors:
- Shuhua Chen
- Jie Yang
- Hong Xiang
- Wei Chen
- Hua Zhong
- Guoping Yang
- Ting Fang
- Hao Deng
- Hong Yuan
- Alex F. Chen
- Hongwei Lu
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Affiliations: Center for Experimental Medical Research, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, P.R. China
Pages: 1103-1108
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Published online on: February 12, 2015

https://doi.org/10.3892/ijmm.2015.2100
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Abstract

The hyperglycemia-induced production of oxidative stress results in endothelial cell dysfunction. Previous studies have demonstrated that sphingosine-1-phosphate (S1P) regulates an array of biological activities in endothelial cells mediated by sphingosine-1-phosphate receptors (S1PRs). However, the role of S1PR-mediated signaling pathways in hyperglycemia-induced endothelial cell dysfunction is currently unknown. In the present study, we aimed to explore the role of S1PRs in endothelial cell dysfunction. For this purpose, hyperglycemia-induced oxidative stress was examined using human umbilical vein endothelial cells (HUVECs) cultured with either normal (5.6 mM) or high (25 mM) levels of glucose. The levels of reactive oxygen species (ROS) and nitric oxide (NO) were determined by flow cytometric (FCM) analysis and nitrate reductase, respectively. Endothelial morphogenesis assay was performed in three-dimensional Matrigel. The mRNA and protein expression levels of S1PRs in the HUVECs were determined by RT-qPCR and western blot analysis, respectively. In addition, ROS, NO and endothelial morphogenesis assays were conducted using the high glucose-treated endothelial cells transfected with adenoviral vector expressing exogenous S1PR1 gene (pAd-S1PR1) or with adenoviral vector expressing S1PR2-specific shRNA (pAd-shRNA-S1PR2). The expression levels of S1PR1 and S1PR2 in the endothelial cells treated with high levels of glucose decreased and increased, respectively. However, the effects of high levels of glucose on S1PR3 were minimal. In addition, high levels of glucose enhanced ROS generation and markedly reduced NO generation and morphogenetic responses. Nevertheless, all the aforementioned changes were completely reversed by transfection with pAd-S1PR1 or pAd-shRNA-S1PR2, which increased S1PR1 and decreased S1PR2 expression, respectively. It can thus be concluded that S1PR1 and S1PR2 play crucial roles in hyperglycemia-induced endothelial cell dysfunction.

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