title: Glucocorticoid excess induces superoxide production in vascular endothelial cells and elicits vascular endothelial dysfunction.
abstract: Glucocorticoid (GC) excess often elicits serious adverse effects on the vascular system, such as hypertension and atherosclerosis, and effective prophylaxis for these complications is limited. We sought to reveal the mechanism underlying GC-induced vascular complications. Responses in forearm blood flow to reactive hyperemia in 20 GC-treated patients were significantly decreased to 43+/-8.9% (mean+/-SEM) from the values obtained before GC therapy (130+/-14%). An administration of vitamin C almost normalized blood flow responses. In human umbilical vein endothelial cells (HUVECs), production of hydrogen peroxide was increased up to 166.5+/-3.3% of control values by 10(-7) mol/L dexamethasone (DEX) treatment (P<0.01). Concomitant with DEX-induced hydrogen peroxide production, intracellular amounts of peroxynitrite significantly increased and those of nitric oxide (NO) decreased, respectively (P<0.01). Immunoblotting analysis using anti-nitrotyrosine antibody showed that peroxynitrite formation was increased in DEX-treated HUVECs. Using inhibitors against metabolic pathways for generation of reactive oxygen species (ROS), we identified that the major production sources of ROS by DEX treatment were mitochondrial electron transport chain, NAD(P)H oxidase, and xanthine oxidase. These findings suggest that GC excess causes overproduction of ROS and thereby perturbs NO availability in the vascular endothelium, leading to vascular complications in patients with GC excess.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Iuchi
authors.forename: Masashi
authors.initials: M
authors.lastname: Akaike
authors.forename: Takao
authors.initials: T
authors.lastname: Mitsui
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ohshima
authors.forename: Yasumi
authors.initials: Y
authors.lastname: Shintani
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Azuma
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000975:Antioxidants / Q000494:pharmacology; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000503:physiopathology*; D002478:Cells, Cultured; D003907:Dexamethasone / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D004579:Electron Transport / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000098:blood supply / Q000737:chemistry / Q000473:pathology; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D030421:Peroxynitrous Acid / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis; D014664:Vasodilation / Q000187:drug effects; D014969:Xanthine Oxidase / Q000378:metabolism
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D013481:Superoxides; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D003907:Dexamethasone; D006861:Hydrogen Peroxide; D014969:Xanthine Oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases