This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 102/1/95    most recent CIRCRESAHA.107.155028v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Romero, M. J. Articles by Caldwell, R. W. Search for Related Content PubMed PubMed Citation Articles by Romero, M. J. Articles by Caldwell, R. W. Related Collections Coronary circulation Cardiovascular Pharmacology Type 1 diabetes Endothelium/vascular type/nitric oxide Related Article

(Circulation Research. 2008;102:95.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Diabetes-induced Coronary Vascular Dysfunction Involves Increased Arginase Activity

Maritza J. Romero, Daniel H. Platt, Huda E. Tawfik, Mohamed Labazi, Azza B. El-Remessy, Manuela Bartoli, Ruth B. Caldwell, Robert W. Caldwell

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. A.B.E.-R. is currently at the College of Pharmacy, University of Georgia, Augusta. M.B. is currently at the Department of Ophthalmology, University of South Carolina School of Medicine, Columbia.

Correspondence to R. William Caldwell, PhD, Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA 30912. 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 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 NO synthase.

Key Words: arginine • coronary arteries • diabetes • endothelial nitric oxide synthase • oxidative stress • vascular endothelial function • vasodilation

Related Article:

Sweet and Sour: Unraveling Diabetic Vascular Disease

Thomas F. Luscher and Jan Steffel
Circ. Res. 2008 102: 9-11. [Full Text] [PDF]

This article has been cited by other articles:

				P. M. Vanhoutte Arginine and Arginase: Endothelial NO Synthase Double Crossed? Circ. Res., April 25, 2008; 102(8): 866 - 868. [Full Text] [PDF]

				S. Ryoo, G. Gupta, A. Benjo, H. K. Lim, A. Camara, G. Sikka, H. K. Lim, J. Sohi, L. Santhanam, K. Soucy, et al. Endothelial Arginase II: A Novel Target for the Treatment of Atherosclerosis Circ. Res., April 25, 2008; 102(8): 923 - 932. [Abstract] [Full Text] [PDF]

				T. F. Luscher and J. Steffel Sweet and Sour: Unraveling Diabetic Vascular Disease Circ. Res., January 4, 2008; 102(1): 9 - 11. [Full Text] [PDF]