Glucocorticoid Excess Induces Superoxide Production in Vascular Endothelial Cells and Elicits Vascular Endothelial Dysfunction

• Published in: Circulation research Vol. 92; no. 1; pp. 81 - 87
• Main Authors: Iuchi, Takahiko, Akaike, Masashi, Mitsui, Takao, Ohshima, Yasushi, Shintani, Yasumi, Azuma, Hiroyuki, Matsumoto, Toshio
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 10.01.2003; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Adolescent; Adult; Aged; Antioxidants - pharmacology; Autoimmune Diseases - drug therapy; Autoimmune Diseases - physiopathology; Biological and medical sciences; Cells, Cultured; Dexamethasone - adverse effects; Dexamethasone - pharmacology; Dexamethasone - therapeutic use; Drug toxicity and drugs side effects treatment; Electron Transport - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - pathology; Endothelium, Vascular - physiopathology; Enzyme Inhibitors - pharmacology; Female; Forearm - blood supply; Glucocorticoids - adverse effects; Glucocorticoids - pharmacology; Glucocorticoids - therapeutic use; Humans; Hydrogen Peroxide - metabolism; Male; Medical sciences; Middle Aged; Muscle, Skeletal - blood supply; Muscle, Skeletal - chemistry; Muscle, Skeletal - pathology; NADH, NADPH Oxidoreductases - metabolism; NADPH Oxidases; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Peroxynitrous Acid - metabolism; Pharmacology. Drug treatments; Reactive Oxygen Species - antagonists & inhibitors; Reactive Oxygen Species - metabolism; Regional Blood Flow - drug effects; Superoxides - metabolism; Toxicity: cardiovascular system; Tyrosine - analogs & derivatives; Tyrosine - analysis; Vasodilation - drug effects; Xanthine Oxidase - metabolism; Human; Endothelial cell; Toxicity; Biosynthesis; Glucocorticoid; In vitro; Free radical; Dose activity relation; In vivo; Hyperoxides; vascular endothelial function; Cell line; Dysfunction; Nitric oxide; Blood vessel; reactive oxygen species; Circulatory system; Umbilical cord
• DOI: 10.1161/01.RES.0000050588.35034.3C
• ISSN: 0009-7330

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 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.