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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:1632.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

A Specific Role for eNOS-Derived Reactive Oxygen Species in Atherosclerosis Progression

Tomofumi Takaya; Ken-ichi Hirata; Tomoya Yamashita; Masakazu Shinohara; Naoto Sasaki; Nobutaka Inoue; Toyotaka Yada; Masami Goto; Akiko Fukatsu; Toshio Hayashi; Nicholas J. Alp; Keith M. Channon; Mitsuhiro Yokoyama; Seinosuke Kawashima

From the Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine (T.T., K.H., T. Yamashita, M.S., N.S., N.I., M.Y., S.K.), Kobe University Graduate School of Medicine, Kobe, Japan; the Department of Medical Engineering and Systems Cardiology (T. Yada, M.G.), Kawasaki Medical School, Kurashiki, Japan; the Department of Geriatrics (A.F., T.H.), Nagoya University Graduate School of Medicine, Nagoya, Japan; the Department of Cardiovascular Medicine (N.J.A., K.M.C.), University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; and the Department of General Medicine (S.K.), Saiseikai Nakatsu Hospital, Osaka, Japan.

Correspondence to Seinosuke Kawashima MD, PhD, Department of General Medicine, Saiseikai Nakatsu Hospital, 2-10-39, Shibata, Kita-ku, Osaka, 530-0012, Japan. E-mail kawashima1008{at}nakatsu.saiseikai.or.jp

Objective— When the availability of tetrahydrobiopterin (BH4) is deficient, endothelial nitric oxide synthase (eNOS) produces superoxide rather than NO (uncoupled eNOS). We have shown that the atherosclerotic lesion size was augmented in apolipoprotein E–deficient (ApoE-KO) mice overexpressing eNOS because of the enhanced superoxide production. In this study, we addressed the specific importance of uncoupled eNOS in atherosclerosis, and the potential mechanistic role for specific versus nonspecific antioxidant strategies in restoring eNOS coupling.

Methods and Results— We crossed mice overexpressing eNOS in the endothelium (eNOS-Tg) with mice overexpressing GTP-cyclohydrolase I (GCH), the rate-limiting enzyme in BH4 synthesis, to generate ApoE-KO/eNOS-Tg/GCH-Tg mice. As a comparison, ApoE-KO/eNOS-Tg mice were treated with vitamin C. Atherosclerotic lesion formation was increased in ApoE-KO/eNOS-Tg mice compared with ApoE-KO mice. GCH overexpression in ApoE-KO/eNOS-Tg/GCH-Tg mice increased vascular BH4 levels and reduced plaque area. This reduction was associated with decreased superoxide production from uncoupled eNOS. Vitamin C treatment failed to reduce atherosclerotic lesion size in ApoE-KO/eNOS-Tg mice, despite reducing overall vascular superoxide production.

Conclusion— In contrast to vitamin C treatment, augmenting BH4 levels in the endothelium by GCH overexpression reduced the accelerated atherosclerotic lesion formation in ApoE-KO/eNOS-Tg mice, associated with a reduction of superoxide production from uncoupled eNOS.

In apolipoprotein E–deficient mice overexpressing eNOS in the endothelium, augmenting BH4 levels in the endothelium by GTP-cyclohydrolase I overexpression was more efficient to reduce the accelerated atherosclerotic lesion formation and superoxide production from uncoupled eNOS compared with chronic vitamin C treatment.

Key Words: eNOS uncoupling • tetrahydrobiopterin • vitamin C • atherosclerosis • apolipoprotein E–deficient mice

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Endothelial GTPCH in eNOS Uncoupling and Atherosclerosis

Tohru Fukai
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