© 2000 American Heart Association, Inc.
Cellular Biology |
Homocysteine Thiolactone and Protein Homocysteinylation in Human Endothelial Cells
Implications for Atherosclerosis
Presented in preliminary form at the Experimental Biology 99 meeting, Washington, DC, April 17–21, 1999, at the symposium "Homocysteine, Aging and Geriatric Disease."
From the Department of Microbiology and Molecular Genetics (H.J.), Hypertension Research Center (L.Z., A.A.), and Department of Obstetrics and Gynecology (A.B.), UMDNJ-New Jersey Medical School, Newark, NJ.
Correspondence to Hieronim Jakubowski, Department of Microbiology and Molecular Genetics, UMDNJ-New Jersey Medical School, 185 S Orange Ave, Newark, NJ 07103. E-mail jakubows{at}umdnj.edu
Abstract—Editing of the nonprotein amino acid homocysteine by certain aminoacyl-tRNA synthetases results in the formation of the thioester homocysteine thiolactone. Here we show that in the presence of physiological concentrations of homocysteine, methionine, and folic acid, human umbilical vein endothelial cells efficiently convert homocysteine to thiolactone. The extent of this conversion is directly proportional to homocysteine concentration and inversely proportional to methionine concentration, suggesting involvement of methionyl-tRNA synthetase. Folic acid inhibits the synthesis of thiolactone by lowering homocysteine and increasing methionine concentrations in endothelial cells. We also show that the extent of post-translational protein homocysteinylation increases with increasing homocysteine levels but decreases with increasing folic acid and HDL levels in endothelial cell cultures. These data support a hypothesis that metabolic conversion of homocysteine to thiolactone and protein homocysteinylation by thiolactone may play a role in homocysteine-induced vascular damage. (Circ Res. 2000;87:45-51.)
Key Words: homocysteine • proteins • HDL lipoproteins • endothelial cells • atherosclerosis
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