Homocysteine Promotes Human Endothelial Cell Dysfunction Via Site-specific Epigenetic Regulation of P66shc

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2011 Sep 22

PMID 21933910

Citations 42

Authors

Cuk-Seong Kim

Young-Rae Kim

Asma Naqvi

Santosh Kumar

Timothy A Hoffman

Saet-Byel Jung

Ajay Kumar

Byeong-Hwa Jeon

Dennis M McNamara

Kaikobad Irani

Affiliations

Soon will be listed here.

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.

Citing Articles

Diet-induced hyperhomocysteinemia causes sex-dependent deficiencies in offspring musculature and brain function.

Suszynska-Zajczyk J, Witucki L, Perla-Kajan J, Jakubowski H Front Cell Dev Biol. 2024; 12:1322844.

PMID: 38559811 PMC: 10979824. DOI: 10.3389/fcell.2024.1322844.

Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.

Zhang Z, Li X, He J, Wang S, Wang J, Liu J J Thromb Thrombolysis. 2023; 56(3):388-397.

PMID: 37466848 DOI: 10.1007/s11239-023-02862-2.

Homocysteine levels in patients with coronary slow flow phenomenon: A meta-analysis.

Yu H, Wang B, Zhao M, Feng F, Li H PLoS One. 2023; 18(7):e0288036.

PMID: 37418362 PMC: 10328313. DOI: 10.1371/journal.pone.0288036.

Epigenetic modifications as therapeutic targets in atherosclerosis: a focus on DNA methylation and non-coding RNAs.

Sum H, Brewer A Front Cardiovasc Med. 2023; 10:1183181.

PMID: 37304954 PMC: 10248074. DOI: 10.3389/fcvm.2023.1183181.

Epi-Drugs in Heart Failure.

Gorica E, Mohammed S, Ambrosini S, Calderone V, Costantino S, Paneni F Front Cardiovasc Med. 2022; 9:923014.

PMID: 35911511 PMC: 9326055. DOI: 10.3389/fcvm.2022.923014.

References

Tang S, Wu M, Wong R, Liu Y, Tang L, Lai C . Epigenetic mechanisms for silencing glutathione S-transferase m2 expression by hypermethylated specificity protein 1 binding in lung cancer. Cancer. 2011; 117(14):3209-21. DOI: 10.1002/cncr.25875. View

Yideng J, Jianzhong Z, Ying H, Juan S, Jinge Z, Shenglan W . Homocysteine-mediated expression of SAHH, DNMTs, MBD2, and DNA hypomethylation potential pathogenic mechanism in VSMCs. DNA Cell Biol. 2007; 26(8):603-11. DOI: 10.1089/dna.2007.0584. View

Devlin A, Singh R, Wade R, Innis S, Bottiglieri T, Lentz S . Hypermethylation of Fads2 and altered hepatic fatty acid and phospholipid metabolism in mice with hyperhomocysteinemia. J Biol Chem. 2007; 282(51):37082-90. DOI: 10.1074/jbc.M704256200. View

Napoli C, Martin-Padura I, de Nigris F, Giorgio M, Mansueto G, Somma P . Deletion of the p66Shc longevity gene reduces systemic and tissue oxidative stress, vascular cell apoptosis, and early atherogenesis in mice fed a high-fat diet. Proc Natl Acad Sci U S A. 2003; 100(4):2112-6. PMC: 149967. DOI: 10.1073/pnas.0336359100. View

Stampfer M, MALINOW M, Willett W, Newcomer L, Upson B, Ullmann D . A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA. 1992; 268(7):877-81. View

Sen U, Tyagi N, Kumar M, Moshal K, Rodriguez W, Tyagi S . Cystathionine-beta-synthase gene transfer and 3-deazaadenosine ameliorate inflammatory response in endothelial cells. Am J Physiol Cell Physiol. 2007; 293(6):C1779-87. DOI: 10.1152/ajpcell.00207.2007. View

Francia P, Delli Gatti C, Bachschmid M, Martin-Padura I, Savoia C, Migliaccio E . Deletion of p66shc gene protects against age-related endothelial dysfunction. Circulation. 2004; 110(18):2889-95. DOI: 10.1161/01.CIR.0000147731.24444.4D. View

Loscalzo J . The oxidant stress of hyperhomocyst(e)inemia. J Clin Invest. 1996; 98(1):5-7. PMC: 507392. DOI: 10.1172/JCI118776. View

Geisel J, Schorr H, Heine G, Bodis M, Hubner U, Knapp J . Decreased p66Shc promoter methylation in patients with end-stage renal disease. Clin Chem Lab Med. 2007; 45(12):1764-70. DOI: 10.1515/CCLM.2007.357. View

10.

McCully K . Homocysteine and vascular disease. Nat Med. 1996; 2(4):386-9. DOI: 10.1038/nm0496-386. View

11.

Weiss N, Heydrick S, Zhang Y, Bierl C, Cap A, Loscalzo J . Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine beta-synthase-deficient mice. Arterioscler Thromb Vasc Biol. 2002; 22(1):34-41. DOI: 10.1161/hq1201.100456. View

12.

Eberhardt R, Forgione M, Cap A, Leopold J, Rudd M, Trolliet M . Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest. 2000; 106(4):483-91. PMC: 380245. DOI: 10.1172/JCI8342. View

13.

Starkebaum G, Harlan J . Endothelial cell injury due to copper-catalyzed hydrogen peroxide generation from homocysteine. J Clin Invest. 1986; 77(4):1370-6. PMC: 424498. DOI: 10.1172/JCI112442. View

14.

Lo Y, Wong I, Zhang J, Tein M, Ng M, Hjelm N . Quantitative analysis of aberrant p16 methylation using real-time quantitative methylation-specific polymerase chain reaction. Cancer Res. 1999; 59(16):3899-903. View

15.

Go Y, Jones D . Intracellular proatherogenic events and cell adhesion modulated by extracellular thiol/disulfide redox state. Circulation. 2005; 111(22):2973-80. DOI: 10.1161/CIRCULATIONAHA.104.515155. View

16.

Rhee I, Bachman K, Park B, Jair K, Yen R, Schuebel K . DNMT1 and DNMT3b cooperate to silence genes in human cancer cells. Nature. 2002; 416(6880):552-6. DOI: 10.1038/416552a. View

17.

Wu L, Wu J, Hunt S, James B, Vincent G, Williams R . Plasma homocyst(e)ine as a risk factor for early familial coronary artery disease. Clin Chem. 1994; 40(4):552-61. View

18.

Ventura A, Luzi L, Pacini S, Baldari C, Pelicci P . The p66Shc longevity gene is silenced through epigenetic modifications of an alternative promoter. J Biol Chem. 2002; 277(25):22370-6. DOI: 10.1074/jbc.M200280200. View

19.

Hervouet E, Vallette F, Cartron P . Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. Epigenetics. 2009; 4(7):487-99. DOI: 10.4161/epi.4.7.9883. View

20.

Lonn E, Yusuf S, Arnold M, Sheridan P, Pogue J, Micks M . Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354(15):1567-77. DOI: 10.1056/NEJMoa060900. View