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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1682.)
© 2004 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Asymmetric Dimethylarginine Produces Vascular Lesions in Endothelial Nitric Oxide Synthase–Deficient Mice

Involvement of Renin-Angiotensin System and Oxidative Stress

Osamu Suda; Masato Tsutsui; Tsuyoshi Morishita; Hiromi Tasaki; Susumu Ueno; Sei Nakata; Takashi Tsujimoto; Yumiko Toyohira; Yoshiaki Hayashida; Yasuyuki Sasaguri; Yoichi Ueta; Yasuhide Nakashima; Nobuyuki Yanagihara

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.

Correspondence to Masato Tsutsui MD, PhD, Department of Pharmacology, University of Occupational and Environmental Health, School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan. E-mail mt2498{at}med.uoeh-u.ac.jp

Objective— Asymmetric 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.

This study demonstrates that asymmetrical dimethylarginine (ADMA) causes arteriosclerotic coronary lesions in mice in vivo through mechanisms other than simple inhibition of endothelial NO synthesis. Our findings should contribute to a better understanding of the pathophysiological role of ADMA in arteriosclerosis.

Key Words: asymmetric dimethylarginine • arteriosclerosis • nitric oxide • endothelial nitric oxide synthase • mice

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