Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen.
Elevated levels of homocysteine are associated with an increased risk of atherosclerosis and thrombosis. The reactivity of the sulfhydryl group of homocysteine has been implicated in molecular mechanisms underlying this increased risk. There is also increasingly compelling evidence that thiols react in the presence of nitric oxide (NO) and endothelium-derived relaxing factor (EDRF) to form S-nitrosothiols, compounds with potent vasodilatory and antiplatelet effects. We, therefore, hypothesized that S-nitrosation of homocysteine would confer these beneficial bioactivities to the thiol, and at the same time attenuate its pathogenicity. We found that prolonged (> 3 h) exposure of endothelial cells to homocysteine results in impaired EDRF responses. By contrast, brief (15 min) exposure of endothelial cells, stimulated to secrete EDRF, to homocysteine results in the formation of S-NO-homocysteine, a potent antiplatelet agent and vasodilator. In contrast to homocysteine, S-NO-homocysteine does not support H2O2 generation and does not undergo conversion to homocysteine thiolactone, reaction products believed to contribute to endothelial toxicity. These results suggest that the normal endothelium modulates the potential, adverse effects of homocysteine by releasing EDRF and forming the adduct S-NO-homocysteine. The adverse vascular properties of homocysteine may result from an inability to sustain S-NO formation owing to a progressive imbalance between the production of NO by progressively dysfunctional endothelial cells and the levels of homocysteine.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
J S
JS
Stamler
J A
JA
Osborne
O
O
Jaraki
L E
LE
Rabbani
M
M
Mullins
D
D
Singel
J
J
Loscalzo
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D002417:Cattle; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D003300:Copper / Q000494:pharmacology; D006152:Cyclic GMP / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology*; D006710:Homocysteine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006711:Homocystine / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D066298:In Vitro Techniques; D007501:Iron / Q000494:pharmacology; D007700:Kinetics; D008163:Luminescent Measurements; D009682:Magnetic Resonance Spectroscopy; D008955:Models, Cardiovascular; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D009589:Nitrogen Oxides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*
D009589:Nitrogen Oxides; D010975:Platelet Aggregation Inhibitors; D006710:Homocysteine; D009569:Nitric Oxide; D006711:Homocystine; D000244:Adenosine Diphosphate; D003300:Copper; D003094:Collagen; D006861:Hydrogen Peroxide; D007501:Iron; D006152:Cyclic GMP