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

Area of Science:

• Vascular Biology
• Epigenetics
• Molecular Medicine

Background:

• Endothelial dysfunction is a critical early event in atherosclerosis.
• The cystathionine-γ-lyase (CSE)/hydrogen sulfide (H2S) system exerts protective effects on endothelial function.
• Oxidized low-density lipoprotein (oxLDL) contributes to endothelial dysfunction.

Purpose of the Study:

• To investigate the role of Ten-eleven translocation-2 (TET2) in oxidized low-density lipoprotein (oxLDL)-induced human umbilical vein endothelial cell (HUVEC) dysfunction.
• To determine the involvement of the CSE/H2S system in TET2-mediated protection against endothelial dysfunction.

Main Methods:

• Utilized TET2 overexpression and knockdown (shRNA) in HUVECs.
• Assessed the impact of oxLDL on TET2 and CSE/H2S system expression.
• Investigated the effect of TET2 on NF-κB activation, ICAM-1, VCAM-1 expression, and THP-1 cell adhesion.
• Examined DNA methylation status and 5-hydroxymethylcytosine (5hmC) levels at the CSE gene promoter.
• Employed CSE siRNA to confirm the role of the CSE/H2S system.

Main Results:

• Oxidized low-density lipoprotein (oxLDL) treatment downregulated TET2 and the CSE/H2S system in HUVECs.
• TET2 overexpression protected HUVECs from oxLDL-induced dysfunction, while TET2 knockdown exacerbated it.
• TET2 upregulated the CSE/H2S system, inhibited NF-κB activation, and reduced inflammatory markers (ICAM-1, VCAM-1) and cell adhesion.
• TET2 promoted DNA demethylation of the CSE gene promoter, increasing CSE expression, an effect dependent on the CSE/H2S system.

Conclusions:

• TET2 exhibits protective effects against oxLDL-induced endothelial dysfunction.
• TET2 upregulates the CSE/H2S system via DNA demethylation of the CSE gene promoter.
• TET2 represents a potential therapeutic target for endothelial dysfunction and associated vascular diseases.