Homocysteine upregulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo.

Circulation Research
Donghong ZhangYi Zhu

Abstract

Hyperhomocysteinemia is a risk factor of atherogenesis. Soluble epoxide hydrolase (sEH) is a major enzyme that hydrolyzes epoxyeicosatrienoic acids and attenuates their cardiovascular protective effects. Whether homocysteine (Hcy) regulates sEH and the underlying mechanism remains elusive. To elucidate the mechanism by which Hcy regulates sEH expression and endothelial activation in vitro and in vivo. Hcy treatment in cultured human endothelial cells dose-dependently and time-dependently upregulated sEH mRNA and protein. Hcy increased the expression of adhesion molecules, which was markedly reversed by inhibiting sEH activity. Hcy-induced sEH upregulation is associated with activation of activating transcription factor-6 (ATF6). Bioinformatics analysis revealed a putative ATF6-binding motif in the promoter region of the sEH gene, which was found at a methylation site. Site-directed mutagenesis and chromatin immunoprecipitation assays demonstrated that Hcy treatment or ATF6 overexpression promoted ATF6 binding to the promoter of sEH and increased its activity. Results of methylation-specific polymerase chain reaction revealed that the ATF6 binding site on the sEH promoter was partially methylated and was demethylated with Hcy. S...Continue Reading

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