title: Alterations in redox homeostasis and prostaglandins impair endothelial-dependent vasodilation in euglycemic autoimmune nonobese diabetic mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ling
authors.forename: Adela
authors.initials: A
authors.lastname: Cota-Gomez
authors.forename: Natalia C
authors.initials: NC
authors.lastname: Flores
authors.forename: Daniel
authors.initials: D
authors.lastname: Hernandez-Saavedra
authors.forename: Joe M
authors.initials: JM
authors.lastname: McCord
authors.forename: John C
authors.initials: JC
authors.lastname: Marecki
authors.forename: Kathryn
authors.initials: K
authors.lastname: Haskins
authors.forename: Marcia
authors.initials: M
authors.lastname: McDuffie
authors.forename: Katherine
authors.initials: K
authors.lastname: Powers
authors.forename: Jennifer
authors.initials: J
authors.lastname: Kench
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Ivan
authors.initials: I
authors.lastname: McMurtry
authors.forename: Sonia C
authors.initials: SC
authors.lastname: Flores
mesh_terms: 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
chemical_list: 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