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Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Editorial Board Member: Gillery, Philippe / Kazmierczak, Steven / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Schlattmann, Peter / Whitfield, John B.

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Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease

Hieronim Jakubowski1

1.

Corresponding author: Hieronim Jakubowski, PhD Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, 225 Warren Street, Newark, NJ 07101-1709, USA Phone: +1-973-972-4483, Fax: +1-973-972-8982,

Citation Information: Clinical Chemical Laboratory Medicine. Volume 43, Issue 10, Pages 1011–1014, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: 10.1515/CCLM.2005.177, September 2005

Publication History

Published Online:
2005-09-30

Abstract

Metabolic conversion of homocysteine (Hcy) to a chemically reactive metabolite, Hcy-thiolactone, catalyzed by methionyl-tRNA synthetase is the first step in a pathway that is suggested to contribute to Hcy toxicity in humans. The accumulation of Hcy-thiolactone is detrimental because of its intrinsic ability to modify proteins by forming N-Hcy-protein adducts, in which a carboxyl group of Hcy is N-linked to the ε-amino group of a protein lysine residue. N-linked Hcy occurs in each protein examined and constitutes a significant pool of Hcy in the blood. N-Hcy proteins are likely to be recognized as neo-self antigens and induce an autoimmune response. Indeed, we found that autoantibodies specific for an -Hcy-Lys epitope on N-Hcy-proteins occur in humans. Serum levels of anti-N-Hcy-protein autoantibodies are directly correlated with plasma tHcy, but not with plasma cysteine or methionine levels. In a group of male patients with stroke, levels of anti-N-Hcy-protein autoantibodies and tHcy were significantly higher than in a group of healthy subjects. In a group of male patients with angiographically documented coronary artery disease, seropositivity for anti-N-Hcy-protein autoantibodies occurred five-fold more frequently than in controls and was an independent predictor of coronary artery disease. These findings show that the formation of N-Hcy-proteins has important physiological consequences and support a hypothesis that N-Hcy-protein is a neo-self antigen that contributes to immune activation, an important modulator of atherogenesis.

Keywords: atherosclerosis; homocysteine-thiolactone; N-homocysteine-protein autoantibodies

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