TET2 Protects against oxLDL-Induced HUVEC Dysfunction by Upregulating the CSE/H2S System.

Juan Peng,Bei He,Zhong Ren,Dang-Heng Wei,Lu-Shan Liu,Zhi-Sheng Jiang,Zhi-Han Tang,Yun Zeng,Xi-Long Zheng,Zuo Wang

doi:10.3389/fphar.2017.00486

Abstract

Ten-eleven translocation-2 (TET2) protein is a DNA demethylase that regulates gene expression through DNA demethylation and also plays important roles in various diseases including atherosclerosis. Endothelial dysfunction represents an early key event in atherosclerotic disease. The cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) is a key endogenous system with protective effects on endothelial functions. In this study, we examined how TET2 regulates oxidized low-density lipoprotein (oxLDL)-induced dysfunction of human umbilical vein endothelial cells (HUVECs) and determined the role of the CSE/H2S system. Treatment with oxLDL resulted in downregulation of both TET2 expression and CSE/H2S system in HUVECs. TET2 was found to have protective effects on oxLDL-induced HUVEC dysfunction, which was confirmed with TET2 overexpression plasmid or TET2 shRNA plasmid. Moreover, TET2 was found to upregulate the CSE/H2S system and inhibit NF-κB activation, leading to decreased expression of ICAM-1 and VCAM-1 and attenuated adhesion of THP-1 cells to oxLDL-activated HUVECs. The protective effect of TET2 was reduced by treatment with CSE siRNA. Further studies revealed that CSE promoter region contains a well-defined CpG island. We also showed that TET2 enhanced 5-hydroxymethylcytosine (5hmC) level and promoted DNA demethylation of CSE gene promoter, leading to an increase in CSE expression. In conclusion, TET2 has protective effects on oxLDL-induced HUVEC dysfunction, likely through upregulating the CSE/H2S system by DNA demethylation of CSE gene promoter. TET2 may become a novel therapeutic target for endothelial dysfunction-associated vascular diseases.

Highlights

Atherosclerosis is a common pathological etiology of various cardiovascular diseases (Glass and Witztum, 2001)
The above results revealed that the downregulation of the CSE/H2S system in oxidized low-density lipoprotein (oxLDL)-stimulated human umbilical vein endothelial cells (HUVECs) was consistent with the alteration of Ten-eleven translocation-2 (TET2) expression
The level of 5hmC was enhanced by TET2 overexpression plasmid and decreased by TET2 shRNA plasmid (Figure 6D). These results suggest that TET2 could upregulate CSE expression via DNA demethylation, resulting in an increased production of H2S in oxLDL-treated HUVECs

Summary

Introduction

Atherosclerosis is a common pathological etiology of various cardiovascular diseases (Glass and Witztum, 2001). It is well accepted that vascular endothelial dysfunction is the initial event in atherosclerosis (Davignon and Ganz, 2004; Landmesser et al, 2004). TET2 Upregulates the CSE/H2S System lipoprotein (oxLDL) is an important pathogenic factor associated with endothelial dysfunction in atherosclerosis (Mitra et al, 2011). OxLDL stimulates endothelial cells to secrete a variety of adhesion molecules and chemotactic factors and promotes the adhesion of monocytes to endothelial cells, leading to the migration to the intima (Devaraj and Jialal, 1996; Itabe, 2009). The monocytes in the intima differentiate into macrophages, which phagocytize excess lipids, leading to the formation of foam cells (Steinberg and Witztum, 2010; Ley et al, 2011)

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