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Relationship of impairment induced by intracellular S-adenosylhomocysteine accumulation with DNA methylation in human umbilical vein endothelial cells treated with 3-deazaadenosine.

Abstract：

:The aim of this study was to estimate the relationship of endothelial dysfunction induced by intracellular S-adenosylhomocysteine (SAH) accumulation and DNA methylation in human umbilical vein endothelial cells (HUVEC). The isolated HUVEC were incubated with 3-deazaadenosine (DZA) to induce experimental intracellular SAH accumulation. The impairment of HUVEC function was assessed by changes in morphology and proliferative ability. The expression of DNA methyltransferase-1 (DNMT1) and the atherosclerosis related genes [oestrogen receptor-alpha (ER-alpha), extracellular superoxide dismutase (EC-SOD) and monocyte chemoattractant protein-1 (MCP-1)] were analysed using quantitative real-time PCR. Global DNA methylated status was measured using the cytosine extension assay. The methylated patterns of ER-alpha, EC-SOD and MCP-1 genes were determined with methylation-specific PCR. We found that DZA administration increased intracellular SAH levels progressively and simultaneously decreased Hcy content in medium. Moreover, the supplementation induced HUVEC apoptosis, inhibited proliferation ability and DNMT1 mRNA expression (P < 0.05) and furthermore reduced global DNA methylation status (P < 0.05). Correlation analysis showed the presence of a negative correlation between intracellular SAH concentration, proliferative ability, and expression of ER-alpha, EC-SOD, and DNMT1 (r = -0.89, -0.86, -0.92 and -0.88 respectively, P < 0.001); and a positive correlation with MCP-1 expression and DNA [(3)H]-dCTP incorporation (r = 0.89 and 0.93 respectively, P < 0.001). Our results showed that endothelial dysfunction induced by intracellular SAH accumulation is mediated by regulating the expression of atherosclerosis related genes in HUVEC, which is not related with gene promoter methylated patterns, but may be associated with altered global DNA hypomethylated status. These findings suggest that SAH can act as the potential molecular biological marker in the promotion of atherogenesis.

journal_name

Int J Exp Pathol

journal_title

International journal of experimental pathology

authors

Yu X,Ling W,Mi M

doi

10.1111/j.1365-2613.2009.00687.x

subject

Has Abstract

pub_date

2009-12-01 00:00:00

pages

638-48

issue

eissn

0959-9673

issn

1365-2613

pii

IEP687

journal_volume

pub_type

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Relationship of impairment induced by intracellular S-adenosylhomocysteine accumulation with DNA methylation in human umbilical vein endothelial cells treated with 3-deazaadenosine.