Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc.

Abstract:

AIMS:Hyperhomocysteinaemia is an independent risk factor for atherosclerotic vascular disease and is associated with vascular endothelial dysfunction. Homocysteine modulates cellular methylation reactions. P66shc is a protein that promotes oxidative stress whose expression is governed by promoter methylation. We asked if homocysteine induces endothelial p66shc expression via hypomethylation of CpG dinucleotides in the p66shc promoter, and whether p66shc mediates homocysteine-stimulated endothelial cell dysfunction. METHODS AND RESULTS:Homocysteine stimulates p66shc transcription in human endothelial cells and hypomethylates specific CpG dinucleotides in the human p66shc promoter. Knockdown of p66shc inhibits the increase in reactive oxygen species, and decrease in nitric oxide, elicited by homocysteine in endothelial cells and prevents homocysteine-induced up-regulation of endothelial intercellular adhesion molecule-1. In addition, knockdown of p66shc mitigates homocysteine-induced adhesion of monocytes to endothelial cells. Inhibition of DNA methyltransferase activity or knockdown of DNA methyltransferase 3b abrogates homocysteine-induced up-regulation of p66shc. Comparison of plasma homocysteine in humans with coronary artery disease shows a significant difference between those with highest and lowest p66shc promoter CpG methylation in peripheral blood leucocytes. CONCLUSION:Homocysteine up-regulates human p66shc expression via hypomethylation of specific CpG dinucleotides in the p66shc promoter, and this mechanism is important in homocysteine-induced endothelial cell dysfunction.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Kim CS,Kim YR,Naqvi A,Kumar S,Hoffman TA,Jung SB,Kumar A,Jeon BH,McNamara DM,Irani K

doi

10.1093/cvr/cvr250

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

466-75

issue

3

eissn

0008-6363

issn

1755-3245

pii

cvr250

journal_volume

92

pub_type

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