Alterations in redox homeostasis and prostaglandins impair endothelial-dependent vasodilation in euglycemic autoimmune nonobese diabetic mice.
We report herein the novel observation that alterations in oxidant/antioxidant balance are evident and cause vascular dysfunction in aortae of prediabetic nonobese-diabetic mice (NOD). We found that nitrotyrosine, a biochemical marker of oxidant stress, was higher in the NOD aortae when compared to age-matched non-autoimmune BALB/c controls or the diabetes-resistant NOD congenic strain, NOD.Lc7. The oxidant stress was localized to the intimal and medial layers, and endothelium-dependent relaxation to acetylcholine was decreased in isolated aortic rings from NOD mice. Inhibition of nitric oxide synthesis caused an endothelium-dependent contraction, and treatment with either a selective thromboxane A2/prostaglandin H2 receptor antagonist or a non-isozyme-specific cyclooxygenase inhibitor reversed this effect. Aortic rings from NOD.Lc7 did not display the paradoxical vasoconstriction. Furthermore, the vascular dysfunction was caused by oxidative stress, as treatment with a superoxide dismutase mimetic in vivo or with native antioxidant enzymes ex vivo inhibited the tissue oxidant stress and restored endothelium-dependent relaxation. Endothelial function was also restored by the inhibitors of NAD(P)H oxidase, diphenylene iodonium or apocynin. Our studies indicate that an oxidant stress that occurs prior to the onset of diabetes in this mouse model contributes to endothelial dysfunction independently of overt diabetes.
Ling
Xiaofeng
X
Webb-Waring Institute for Cancer, Aging and Antioxidant Research, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Box C-321, Denver, CO 80262, USA.
Cota-Gomez
Adela
A
Flores
Natalia C
NC
Hernandez-Saavedra
Daniel
D
McCord
Joe M
JM
Marecki
John C
JC
Haskins
Kathryn
K
McDuffie
Marcia
M
Powers
Katherine
K
Kench
Jennifer
J
Oka
Masahiko
M
McMurtry
Ivan
I
Flores
Sonia C
SC
D000098:Acetophenones / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology*; D006706:Homeostasis; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D009861:Onium Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011236:Prediabetic State / Q000378:metabolism / Q000503:physiopathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism; D014664:Vasodilation
D000098:Acetophenones; D016861:Cyclooxygenase Inhibitors; D009861:Onium Compounds; D011453:Prostaglandins; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; C007517:diphenyleneiodonium; C056165:acetovanillone; D011451:Prostaglandin-Endoperoxide Synthases; D019255:NADPH Oxidases; D000109:Acetylcholine