Published online before print October 25, 2007, doi: 10.1161/CIRCRESAHA.107.155028
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Submitted on April 27, 2007
Revised on September 5, 2007
Accepted on October 15, 2007
Diabetes-Induced Coronary Vascular Dysfunction Involves Increased Arginase Activity
Maritza J. Romero ;
From the Department of Pharmacology & Toxicology (M.J.R., D.H.P., H.E.T., A.B.E.-R., R.W.C.), Vascular Biology Center (M.L., M.B., R.B.C.), and Department of Cellular Biology and Anatomy (R.B.C.), Medical College of Georgia, Augusta.
* To whom correspondence should be addressed. E-mail: wcaldwel{at}mail.mcg.edu.
Increases in arginase activity have been reported in a variety of disease conditions characterized by vascular dysfunction. Arginase competes with NO synthase (NOS) for their common substrate arginine, suggesting a cause and effect relationship. We tested this concept by experiments with streptozotocin diabetic rats and high glucose (HG)-treated bovine coronary endothelial cells (BCECs). Our studies showed that diabetes-induced impairment of vasorelaxation to acetylcholine was correlated with increases in reactive oxygen species and arginase activity and arginase I expression in aorta and liver. Treatment of diabetic rats with simvastatin (5 mg/kg per day, subcutaneously) or L-citrulline (50 mg/kg per day, orally) blunted these effects. Acute treatment of diabetic coronary arteries with arginase inhibitors also reversed the impaired vasodilation to acetylcholine. Treatment of BCECs with HG (25 mmol/L, 24 hours) also increased arginase activity. This effect was blocked by treatment with simvastatin (0.1 µmol/L), the Rho kinase inhibitor Y-27632 (10 µmol/L), or L-citrulline (1 mmol/L). Superoxide and active RhoA levels also were elevated in HG-treated BCECs. Furthermore, HG significantly diminished NO production in BCECs. Transfection of BCECs with arginase I small interfering RNA prevented the rise in arginase activity in HG-treated cells and normalized NO production, suggesting a role for arginase I in reduced NO production with HG. These results indicate that increased arginase activity in diabetes contributes to vascular endothelial dysfunction by decreasing L-arginine availability to NOS.
Key words: arginine • coronary arteries • diabetes • endothelial nitric oxide synthase • oxidative stress • vascular endothelial function • vasodilation
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