Arginase promotes neointima formation in rat injured carotid arteries.
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.


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 G(0)/G(1) phase of the cell cycle and induced the expression of the cyclin-dependent protein kinase inhibitor, p21.


CONCLUSIONS
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.
Peyton
Kelly J
KJ
Department of Medical Pharmacology and Physiology, School of Medicine, University of Missouri-Columbia, Columbia, MO 65212, USA.
Ensenat
Diana
D
Azam
Mohammed A
MA
Keswani
Amit N
AN
Kannan
Sankaranarayanan
S
Liu
Xiao-ming
XM
Wang
Hong
H
Tulis
David A
DA
Durante
William
W
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001897:Boronic Acids / Q000494:pharmacology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000473:pathology; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004195:Disease Models, Animal; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology* / Q000293:injuries / Q000473:pathology; D015854:Up-Regulation
C425062:(2-boronoethyl)-cysteine; D001897:Boronic Acids; C493958:Cdkn1a protein, rat; D050759:Cyclin-Dependent Kinase Inhibitor p21; C404735:N(omega)-hydroxynorarginine; D034741:RNA, Small Interfering; D001120:Arginine; D001119:Arginase