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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:488.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Arginase Promotes Neointima Formation in Rat Injured Carotid Arteries

Kelly J. Peyton; Diana Ensenat; Mohammed A. Azam; Amit N. Keswani; Sankaranarayanan Kannan; Xiao-ming Liu; Hong Wang; David A. Tulis; William Durante

From the Department of Medical Pharmacology and Physiology (K.J.P., M.A.A., S.K., X.L., W.D.), School of Medicine, University of Missouri, Columbia; the Department of Medicine (K.J.P., D.E., A.N.K., S.K., X.L., W.D.), Baylor College of Medicine, Houston, Tex; the Department of Pharmacology (H.W.), Temple University, Philadelphia, Pa; the J.L. Chambers Biomedical/Biotechnology Research Institute and Department of Biology (D.A.T.), North Carolina Central University, Durham; and the Department of Physiology (D.A.T.), Brody School of Medicine, East Carolina University, Greenville, NC.

Correspondence to William Durante, PhD, Department of Medical Pharmacology and Physiology, M409 Medical Sciences Building, University of Missouri-Columbia, One Hospital Drive, Columbia, MO 65212. E-mail durantew{at}health.missouri.edu

Objective— Arginase stimulates the proliferation of cultured vascular smooth muscle cells (VSMCs); however, the influence of arginase on VSMC growth in vivo is not known. This study investigated the impact of arginase on cell cycle progression and neointima formation after experimental arterial injury.

Methods and Results— Balloon injury of rat carotid arteries resulted in a sustained increase in arginase activity in the vessel wall and the induction of arginase I protein in both the media and neointima of injured vessels. Furthermore, local perivascular application of the potent and selective arginase inhibitors S-(2-boronoethyl)-L-cysteine (BEC) or N^G-hydroxy-nor-L-arginine (L-OHNA) immediately after injury markedly attenuated medial and neointimal DNA synthesis and neointima formation. Substantial arginase I protein and arginase activity was also detected in rat cultured aortic VSMCs. Moreover, treatment of VSMCs with BEC or L-OHNA, or knockdown of arginase I protein, arrested cells in the G₀/G₁ phase of the cell cycle and induced the expression of the cyclin-dependent protein kinase inhibitor, p21.

Conclusion— This study demonstrates that arginase is essential for VSMCs to enter the cell cycle and that arginase I contributes to the remodeling response after arterial injury. Arginase I represents a potentially new therapeutic target for the treatment of vasculoproliferative disorders.

Arginase is the central enzyme of the urea cycle that converts L-arginine to L-ornithine and urea. We now report that arginase contributes to cell cycle progression and neointima formation after arterial injury, and identify arginase as a promising therapeutic target in treating vasculoproliferative disorders.

Key Words: arginase • vascular smooth muscle cell proliferation • neointima