Abstract
Hydrogen sulfide (H 2 S), mainly produced by cystathionine-gamma-lyase (CSE) in vascular system, emerges as a novel gasotransmitter and exerts anti-atherosclerotic effects. Alterations of CSE/H 2 S pathway may thus be implicated in atherogenesis. However, the cellular and molecular mechanisms remain to be clarified. In this study, we showed that ox-LDL, the major risk factor of atherosclerosis, suppressed CSE promoter activity, and decreased its mRNA and protein expression, as well as H 2 S generation in macrophage. Exogenous H 2 S and CSE overexpression reduced TNF-alpha and ICAM-1 generation in ox-LDL-treated macrophage and its adhesion to the endothelial monolayer, whilst CSE knockdown produced opposite effects. Interestingly, ox-LDL increased the expression and activity of DNA methyltransferase (DNMT) and resulted in hypermethylation of CpG islands in the cse gene promoter region, as determined by mehylation-specific PCR and bisulfate sequencing. Moreover, DNMT inhibitor 5-aza-2′-deoxycytidine and DNMT1 siRNA abolished the CSE decrease induced by ox-LDL. More important, the ox-LDL-induced disturbance of CSE and DNMT was confirmed in the peritoneal macrophage isolated from ApoE −/− mice. These results reveal that DNA hypermethylation may be involved in ox-LDL induced CSE downregulation and subsequent H 2 S reduction in macrophage. We conclude that ox-LDL activates macrophage and triggers vascular inflammation by suppressing CSE transcription via its promoter region hypermethylation.
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