on June 24, 2004
Published online before print June 24, 2004, doi: 10.1161/01.ATV.0000136656.26019.6e
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Submitted on March 16, 2004
Accepted on May 30, 2004
Asymmetric Dimethylarginine Causes Arteriosclerotic Lesions in Endothelial Nitric Oxide Synthase-Deficient Mice. Involvement of Renin-Angiotensin System and Oxidative Stress
Osamu Suda ;
From the Second Department of Internal Medicine (O.S., T.M., H.T., S.N., Y.N.), and the Departments of Pharmacology (M.T., S.U., T.T., Y.T., N.Y.), Systems Physiology (Y.H.), Pathology (Y.S.), and Physiology (Y.U.), University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan.
* To whom correspondence should be addressed. E-mail: mt2498{at}med.uoeh-u.ac.jp.
Objective--Asymmetrical dimethylarginine (ADMA) is widely believed to be an endogenous nitric oxide synthase (eNOS) inhibitor. However, in this study, we examined our hypothesis that the long-term vascular effects of ADMA are not mediated by inhibition of endothelial NO synthesis.
Methods and Results--ADMA was infused in wild-type and eNOS--knockout (KO) mice by osmotic minipump for 4 weeks. In wild-type mice, long-term treatment with ADMA caused significant coronary microvascular lesions. Importantly, in eNOS-KO mice, treatment with ADMA also caused an extent of coronary microvascular lesions that was comparable to that in wild-type mice. These vascular effects of ADMA were not prevented by supplementation of L-arginine, and vascular NO production was not reduced by ADMA treatment. Treatment with ADMA caused upregulation of angiotensin-converting enzyme (ACE) and an increase in superoxide production that were comparable in both strains and that were abolished by simultaneous treatment with temocapril (ACE inhibitor) or olmesartan (AT1 receptor antagonist), which simultaneously suppressed vascular lesion formation.
Conclusions--These results provide the first direct evidence that the long-term vascular effects of ADMA are not solely mediated by simple inhibition of endothelial NO synthesis. Direct upregulation of ACE and increased oxidative stress through AT1 receptor appear to be involved in the long-term vascular effects of ADMA in vivo.
Key words: asymmetrical dimethylarginine • arteriosclerosis • nitric oxide • endothelial nitric oxide synthase • mice
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