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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1068.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Augmentation of Vascular Remodeling by Uncoupled Endothelial Nitric Oxide Synthase in a Mouse Model of Diabetes Mellitus

Naoto Sasaki; Tomoya Yamashita; Tomofumi Takaya; Masakazu Shinohara; Rio Shiraki; Masafumi Takeda; Noriaki Emoto; Akiko Fukatsu; Toshio Hayashi; Kazuhisa Ikemoto; Takahide Nomura; Mitsuhiro Yokoyama; Ken-ichi Hirata; Seinosuke Kawashima

From the Division of Cardiovascular Medicine, Department of Internal Medicine (N.S., T.Y., T.T., M.S., R.S., M.T., N.E., M.Y., K.H., S.K.), Kobe University Graduate School of Medicine, Kobe, Japan; the Department of Geriatrics (A.F., T.H.), Nagoya University Graduate School of Medicine, Nagoya, Japan; the Department of Pharmacology (K.I., T.N.), School of Medicine, Fujita Health University, Aichi, Japan; and the Department of General Medicine (S.K.), Nakatsu Saiseikai Hospital, Osaka, Japan.

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

Objective— Diabetes mellitus is associated with increased oxidative stress, which induces oxidation of tetrahydrobiopterin (BH4) in vessel wall. Without enough BH4, eNOS is uncoupled to L-arginine and produces superoxide rather than NO. We examined the role of uncoupled eNOS in vascular remodeling in diabetes.

Methods and Results— Diabetes mellitus was produced by streptozotocin in C57BL/6J mice. Under stable hyperglycemia, the common carotid artery was ligated, and neointimal formation was examined 4 weeks later. In diabetic mice, the neointimal area was dramatically augmented. This augmentation was associated with increased aortic superoxide formation, reduced aortic BH4/dihydrobiopterin (BH2) ratio, and decreased plasma nitrite and nitrate (NOx) levels compared with nondiabetic mice. Chronic BH4 treatment (10 mg/kg/d) reduced the neointimal area in association with suppressed superoxide production and inflammatory changes in vessels. BH4/BH2 ratio in vessel wall was preserved, and plasma NOx levels increased. Furthermore, in the presence of diabetes, overexpression of bovine eNOS resulted in augmentation of neointimal area, accompanied by increased superoxide production in the endothelium.

Conclusions— In diabetes, increased oxidative stress by uncoupled NOSs, particularly eNOS, causes augmentation of vascular remodeling. These findings indicate restoration of eNOS coupling has an atheroprotective benefit in diabetes.

In streptozotocin-induced diabetic mice, diabetes accelerated vascular remodeling in association with augmented superoxide production from the uncoupled eNOS. Exogenous tetrahydrobiopterin inhibited the augmentation of remodeling process by restoring eNOS coupling. These findings may provide a new crew to therapeutic strategy for diabetic vascular complication.

Key Words: diabetes mellitus • eNOS uncoupling • tetrahydrobiopterin • superoxide • vascular remodeling