Circulation. 2001;104:2569-2575
doi: 10.1161/hc4601.098514
doi: 10.1161/hc4601.098514
(Circulation. 2001;104:2569.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Homocysteine Impairs the Nitric Oxide Synthase Pathway
Role of Asymmetric Dimethylarginine
From the Section of Vascular Medicine, Stanford University, Stanford, Calif (M.C.S., P.S.T., J.P.C.); Panorama Research Incorporated, Mountain View, Calif (J.-H.H., R.F.B.); and the Department of Nutritional Science, Faculty of Health and Welfare Science, Okayama Prefectural University, Okayama, Japan (M.K.).
Correspondence to John P. Cooke, MD, PhD, Stanford University School of Medicine, Falk Cardiovascular Research Center, 300 Pasteur Drive, Stanford, CA 94305-5406. E-mail John.Cooke{at}Stanford.edu
Background Hyperhomocysteinemia is a putative risk factor for cardiovascular disease, which also impairs endothelium-dependent vasodilatation. A number of other risk factors for cardiovascular disease may exert their adverse vascular effects in part by elevating plasma levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase. Accordingly, we determined if homocysteine could increase ADMA levels.
Methods and Results When endothelial or nonvascular cells were exposed to DL-homocysteine or to its precursor L-methionine, ADMA concentration in the cell culture medium increased in a dose- and time-dependent fashion. This effect was associated with the reduced activity of dimethylarginine dimethylaminohydrolase (DDAH), the enzyme that degrades ADMA. Furthermore, homocysteine-induced accumulation of ADMA was associated with reduced nitric oxide synthesis by endothelial cells and segments of pig aorta. The antioxidant pyrrollidine dithiocarbamate preserved DDAH activity and reduced ADMA accumulation. Moreover, homocysteine dose-dependently reduced the activity of recombinant human DDAH in a cell free system, an effect that was due to a direct interaction between homocysteine and DDAH.
Conclusion Homocysteine post-translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium-mediated nitric oxide–dependent vasodilatation.
Key Words: endothelium • arginine • atherosclerosis • nitric oxide
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