Journal article
Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc
Cardiovascular research, Vol.92(3), pp.466-475
12/01/2011
DOI: 10.1093/cvr/cvr250
PMCID: PMC3211975
PMID: 21933910
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.
Details
- Title: Subtitle
- Homocysteine promotes human endothelial cell dysfunction via site-specific epigenetic regulation of p66shc
- Creators
- Cuk-Seong Kim - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USAYoung-Rae Kim - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USAAsma Naqvi - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USASantosh Kumar - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USATimothy A Hoffman - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USASaet-Byel Jung - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USAAjay Kumar - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USAByeong-Hwa Jeon - 3 Department of Physiology, Chungnam National University School of Medicine, Daejeon, Republic of KoreaDennis M McNamara - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USAKaikobad Irani - 1 Heart and Vascular Institute, University of Pittsburgh Medical Center, Scaife S620, 200 Lothrop St, Pittsburgh, PA 15213, USA
- Resource Type
- Journal article
- Publication Details
- Cardiovascular research, Vol.92(3), pp.466-475
- Publisher
- Oxford University Press
- DOI
- 10.1093/cvr/cvr250
- PMID
- 21933910
- PMCID
- PMC3211975
- ISSN
- 0008-6363
- eISSN
- 1755-3245
- Language
- English
- Date published
- 12/01/2011
- Academic Unit
- Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
- Record Identifier
- 9984047865602771
Metrics
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