(Circulation. 1999;99:3092-3095.)
© 1999 American Heart Association, Inc.
Brief Rapid Communications |
Novel Mechanism for Endothelial Dysfunction
Dysregulation of Dimethylarginine Dimethylaminohydrolase
From the Division of Cardiovascular Medicine, Stanford University School of Medicine (A.I., P.S.T., S.A., J.P.C.), Stanford, Calif; the Department of Nutritional Science, Okayama Prefectural University (M.K.), Kuboki, Japan; and Research Institute for Food Science, Kyoto University (T.O.), Uji, Japan.
Correspondence to John P. Cooke, MD, PhD, Associate Professor, Division of Cardiovascular Medicine, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5246. E-mail John.Cooke{at}stanford.edu
Background—Asymmetric
dimethylarginine (ADMA) is an endogenous
inhibitor of nitric oxide synthase (NOS). Plasma levels of
ADMA are elevated in individuals with
hypercholesterolemia or
atherosclerosis. We postulated that reduced degradation
of ADMA may play a role in the accumulation of ADMA in these
individuals. Accordingly, we studied the effects of oxidized LDL
(oxLDL) or tumor necrosis factor-
(TNF-) on the accumulation of
ADMA by transformed human umbilical vein endothelial
cells (ECV304) and on the enzyme dimethylarginine
dimethylaminohydrolase (DDAH), which degrades ADMA.
Methods and Results—ECV304 were incubated with or without native
LDL (100 µg/mL), oxLDL (100 µg/mL), or TNF- (250 U/mL) for 48
hours. The concentration of ADMA in the conditioned medium was
determined by high-performance liquid
chromatography. Western blotting was performed to
evaluate DDAH expression. We assayed DDAH activity by determining
L-citrulline formation from ADMA. The addition of oxLDL or
TNF- to ECV304 significantly increased the level of ADMA in the
conditioned medium. The effect of oxLDL or TNF- was not due to a
change in DDAH expression but rather to the reduction of DDAH activity.
To determine whether dysregulation of DDAH also occurred in vivo, New
Zealand White rabbits were fed normal chow or a
high-cholesterol diet.
Hypercholesterolemia significantly reduced
aortic, renal, and hepatic DDAH activity.
Conclusions—These results suggest that the endothelial vasodilator dysfunction observed in hypercholesterolemia may be due to reduced degradation of ADMA, the endogenous inhibitor of NOS.
Key Words: lipoproteins • endothelium • amino acids • asymmetric dimethylarginine • nitric oxide
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V. Achan, M. Broadhead, M. Malaki, G. Whitley, J. Leiper, R. MacAllister, and P. Vallance Asymmetric Dimethylarginine Causes Hypertension and Cardiac Dysfunction in Humans and Is Actively Metabolized by Dimethylarginine Dimethylaminohydrolase Arterioscler Thromb Vasc Biol, August 1, 2003; 23(8): 1455 - 1459. [Abstract] [Full Text] [PDF]
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J. P. Cooke, K. Sydow, J. Chen, and P. Huang A Peculiar Result and a Fanciful Hypothesis Regarding L-Arginine * Arterioscler Thromb Vasc Biol, June 1, 2003; 23(6): 1128 - 1128. [Full Text] [PDF]
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 D Tousoulis, G J Davies, C Tentolouris, T Crake, G Goumas, C Stefanadis, and P Toutouzas Effects of L-arginine on flow mediated dilatation induced by atrial pacing in diseased epicardial coronary arteries Heart, May 1, 2003; 89(5): 531 - 534. [Abstract] [Full Text] [PDF]
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J. T. Kielstein, S. M. Bode-Boger, J. C. Frolich, E. Ritz, H. Haller, and D. Fliser Asymmetric Dimethylarginine, Blood Pressure, and Renal Perfusion in Elderly Subjects Circulation, April 15, 2003; 107(14): 1891 - 1895. [Abstract] [Full Text] [PDF]
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M. Weis and J. P. Cooke Cardiac Allograft Vasculopathy and Dysregulation of the NO Synthase Pathway Arterioscler Thromb Vasc Biol, April 1, 2003; 23(4): 567 - 575. [Abstract] [Full Text] [PDF]
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S. Ueda, S. Kato, H. Matsuoka, M. Kimoto, S. Okuda, M. Morimatsu, and T. Imaizumi Regulation of Cytokine-Induced Nitric Oxide Synthesis by Asymmetric Dimethylarginine: Role of Dimethylarginine Dimethylaminohydrolase Circ. Res., February 7, 2003; 92(2): 226 - 233. [Abstract] [Full Text] [PDF]
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M. Knipp, O. Braun, P. M. Gehrig, R. Sack, and M. Vasak Zn(II)-free Dimethylargininase-1 (DDAH-1) Is Inhibited upon Specific Cys-S-Nitrosylation J. Biol. Chem., January 24, 2003; 278(5): 3410 - 3416. [Abstract] [Full Text] [PDF]
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 G. E. Mann, D. L. Yudilevich, and L. Sobrevia Regulation of Amino Acid and Glucose Transporters in Endothelial and Smooth Muscle Cells Physiol Rev, January 1, 2003; 83(1): 183 - 252. [Abstract] [Full Text] [PDF]
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 J. Leiper, J. Murray-Rust, N. McDonald, and P. Vallance S-nitrosylation of dimethylarginine dimethylaminohydrolase regulates enzyme activity: Further interactions between nitric oxide synthase and dimethylarginine dimethylaminohydrolase PNAS, October 15, 2002; 99(21): 13527 - 13532. [Abstract] [Full Text] [PDF]
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A. J. Cardounel and J. L. Zweier Endogenous Methylarginines Regulate Neuronal Nitric-oxide Synthase and Prevent Excitotoxic Injury J. Biol. Chem., September 6, 2002; 277(37): 33995 - 34002. [Abstract] [Full Text] [PDF]
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R. Maas, E. Schwedhelm, J. Albsmeier, and R. H Boger The pathophysiology of erectile dysfunction related to endothelial dysfunction and mediators of vascular function Vascular Medicine, August 1, 2002; 7(3): 213 - 225. [Abstract] [PDF]
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N. Weiss, C. Keller, U. Hoffmann, and J. Loscalzo Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia Vascular Medicine, August 1, 2002; 7(3): 227 - 239. [Abstract] [PDF]
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 H. Masuda, T. Tsujii, T. Okuno, K. Kihara, M. Goto, and H. Azuma Accumulated endogenous NOS inhibitors, decreased NOS activity, and impaired cavernosal relaxation with ischemia Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1730 - R1738. [Abstract] [Full Text] [PDF]
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V. Achan, C. T.L. Tran, F. Arrigoni, G. St.J. Whitley, J. M. Leiper, and P. Vallance all-trans-Retinoic Acid Increases Nitric Oxide Synthesis by Endothelial Cells: A Role for the Induction of Dimethylarginine Dimethylaminohydrolase Circ. Res., April 19, 2002; 90(7): 764 - 769. [Abstract] [Full Text] [PDF]
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M. A.W. Broeders, G. J. Tangelder, D. W. Slaaf, R. S. Reneman, and M. G.A. oude Egbrink Hypercholesterolemia Enhances Thromboembolism in Arterioles but Not Venules: Complete Reversal by L-Arginine Arterioscler Thromb Vasc Biol, April 1, 2002; 22(4): 680 - 685. [Abstract] [Full Text] [PDF]
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 D. T. Nash Insulin Resistance, ADMA Levels, and Cardiovascular Disease JAMA, March 20, 2002; 287(11): 1451 - 1452. [Full Text] [PDF]
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 R. O. Cannon III Oral L-arginine (and other active ingredients) for ischemic heart disease? J. Am. Coll. Cardiol., January 2, 2002; 39(1): 46 - 48. [Full Text] [PDF]
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J. T. Kielstein, R. H. Boger, S. M. Bode-Boger, J. C. Frolich, H. Haller, E. Ritz, and D. Fliser Marked Increase of Asymmetric Dimethylarginine in Patients with Incipient Primary Chronic Renal Disease J. Am. Soc. Nephrol., January 1, 2002; 13(1): 170 - 176. [Abstract] [Full Text] [PDF]
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M. C. Stuhlinger, P. S. Tsao, J.-H. Her, M. Kimoto, R. F. Balint, and J. P. Cooke Homocysteine Impairs the Nitric Oxide Synthase Pathway: Role of Asymmetric Dimethylarginine Circulation, November 20, 2001; 104(21): 2569 - 2575. [Abstract] [Full Text] [PDF]
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C. Zhang, R. Patel, J. P. Eiserich, F. Zhou, S. Kelpke, W. Ma, D. A. Parks, V. Darley-Usmar, and C. R. White Endothelial dysfunction is induced by proinflammatory oxidant hypochlorous acid Am J Physiol Heart Circ Physiol, October 1, 2001; 281(4): H1469 - H1475. [Abstract] [Full Text] [PDF]
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H. A. Walker, E. McGing, I. Fisher, R. H. Boger, S. M. Bode-Boger, G. Jackson, J. M. Ritter, and P. J. Chowienczyk Endothelium-dependent vasodilation is independent of the plasma L-arginine/ADMA ratio in men with stable angina: Lack of effect of oral l-arginine on endothelial function, oxidative stress and exercise performance J. Am. Coll. Cardiol., August 1, 2001; 38(2): 499 - 505. [Abstract] [Full Text] [PDF]
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W.-H. Lee, T.-H. Hwang, G. T. Oh, S. U. Kwon, Y.-H. Choi, and J.-E. Park Genetic factors associated with endothelial dysfunction affect the early onset of coronary artery disease in Korean males Vascular Medicine, May 1, 2001; 6(2): 103 - 108. [Abstract] [PDF]
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G. D. Thomas, W. Zhang, and R. G. Victor Nitric Oxide Deficiency as a Cause of Clinical Hypertension: Promising New Drug Targets for Refractory Hypertension JAMA, April 25, 2001; 285(16): 2055 - 2057. [Full Text] [PDF]
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R. H. Boger, S. M. Bode-Boger, P. S. Tsao, P. S. Lin, J. R. Chan, and J. P. Cooke An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes J. Am. Coll. Cardiol., December 1, 2000; 36(7): 2287 - 2295. [Abstract] [Full Text] [PDF]
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G. Wu and C. J. Meininger Arginine Nutrition and Cardiovascular Function J. Nutr., November 1, 2000; 130(11): 2626 - 2629. [Abstract] [Full Text] [PDF]
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J. J. Jang, H.-K. V. Ho, H. H. Kwan, L. F. Fajardo, and J. P. Cooke Angiogenesis Is Impaired by Hypercholesterolemia : Role of Asymmetric Dimethylarginine Circulation, September 19, 2000; 102(12): 1414 - 1419. [Abstract] [Full Text] [PDF]
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J. P. Cooke Does ADMA Cause Endothelial Dysfunction? Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2032 - 2037. [Abstract] [Full Text] [PDF]
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A. Fard, C. H. Tuck, J. A. Donis, R. Sciacca, M. R. Di Tullio, H. D. Wu, T. A. Bryant, N.-T. Chen, M. Torres-Tamayo, R. Ramasamy, et al. Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-Fat Meal in Patients With Type 2 Diabetes Arterioscler Thromb Vasc Biol, September 1, 2000; 20(9): 2039 - 2044. [Abstract] [Full Text] [PDF]
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