Methylation pathway perturbations with folate deficiency: A role for epigenetics in endothelial gene expression.

摘要

Folate deficiency is an independent risk factor for atherosclerotic cardiovascular disease. To better understand how folate deficiency elicits changes in vascular wall homeostasis, we established an endothelial cell model of folate deficiency. Increases in steady-state mRNA levels of the folate receptor-α and γ-glutamyl hydrolase and an accumulation of cell-associated homocysteine and SAE were found. Because SAH can inhibit many SAM-mediated methylation reactions, we assessed DNA and histone methylation pathways. Genomic cytosine methylation levels indicated global DNA hypomethylation. In agreement with recent evidence indicating that folate bioavailability affects a key endothelial phenotype, namely the production of NO, we found a concentration-dependent decrease in eNOS steady-state mRNA levels. Decreased eNOS promoter RNA polymerase II loading and dimethylated H3-K4 suggested the folate deficiency can alter gene expression by inhibiting methyltransferase pathways. This work describes, for the first time, a novel mechanism by which folate deficiency can confer a predisposition to cardiovascular pathology.