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Circulation Research. 2002
Published online before print December 5, 2002, doi: 10.1161/01.RES.0000050588.35034.3C
A more recent version of this article appeared on January 10, 2003
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Submitted on January 23, 2002
Revised on October 30, 2002
Accepted on November 22, 2002

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

Takahiko Iuchi ; Masashi Akaike *; Takao Mitsui ; Yasushi Ohshima ; Yasumi Shintani ; Hiroyuki Azuma ; and Toshio Matsumoto

From the Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, Tokushima, Japan.

* To whom correspondence should be addressed. E-mail: akaike{at}clin.med.tokushima-u.ac.jp.

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.
Key words: glucocorticoid • reactive oxygen species • nitric oxide • vascular endothelial function




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