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 Yokoyariia, Ken Ichi Hirata, Seinosuke Kawashima

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43 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1068-1076
Number of pages9
JournalArteriosclerosis, thrombosis, and vascular biology
Volume28
Issue number6
DOIs
Publication statusPublished - 01-06-2008

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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    Sasaki, N., Yamashita, T., Takaya, T., Shinohara, M., Shiraki, R., Takeda, M., Emoto, N., Fukatsu, A., Hayashi, T., Ikemoto, K., Nomura, T., Yokoyariia, M., Hirata, K. I., & Kawashima, S. (2008). Augmentation of vascular remodeling by uncoupled endothelial nitric oxide synthase in a mouse model of diabetes mellitus. Arteriosclerosis, thrombosis, and vascular biology, 28(6), 1068-1076. https://doi.org/10.1161/ATVBAHA.107.160754