Anti-N-homocysteinylated protein autoantibodies and cardiovascular disease.
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 epsilon-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 Nepsilon-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.
Jakubowski
Hieronim
H
Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, International Center for Public Health, Newark, NJ 07101-1709, USA. jakubows@umdnj.edu
D000818:Animals; D001323:Autoantibodies / Q000276:immunology* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000276:immunology* / Q000378:metabolism*; D003331:Coronary Vessels / Q000276:immunology / Q000378:metabolism; D006710:Homocysteine / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism*; D006801:Humans
D001323:Autoantibodies; D006710:Homocysteine