Augmentation of vascular remodeling by uncoupled endothelial nitric oxide synthase in a mouse model of diabetes mellitus.
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.


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.
Sasaki
Naoto
N
Department of General Medicine, Nakatsu Saiseikai Hospital, 2-10-39 Shibata, Kita-ku, Osaka 530-0012, Japan.
Yamashita
Tomoya
T
Takaya
Tomofumi
T
Shinohara
Masakazu
M
Shiraki
Rio
R
Takeda
Masafumi
M
Emoto
Noriaki
N
Fukatsu
Akiko
A
Hayashi
Toshio
T
Ikemoto
Kazuhisa
K
Nomura
Takahide
T
Yokoyama
Mitsuhiro
M
Hirata
Ken-Ichi
K
Kawashima
Seinosuke
S
D000818:Animals; D001011:Aorta / Q000378:metabolism; D001708:Biopterins / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D002339:Carotid Arteries / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006136:GTP Cyclohydrolase / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D013311:Streptozocin; D013481:Superoxides / Q000378:metabolism
D009566:Nitrates; D009573:Nitrites; D013481:Superoxides; D001708:Biopterins; D013311:Streptozocin; D002784:Cholesterol; D052250:Nitric Oxide Synthase Type III; D006136:GTP Cyclohydrolase; C003402:sapropterin