Regulation of arginase pathway in response to wall shear stress.
OBJECTIVE
Alterations of wall shear stress can predispose the endothelium to the development of atherosclerotic plaques. Ample evidence indicates that arginase expression and/or activity correlates with several risk factors for cardiovascular disease including atherosclerosis. We investigated the regulation of arginase pathway in response to distinct patterns of wall shear stress.


METHODS
Isolated porcine endothelial cells and carotid arterial segments were perfused under unidirectional high shear stress (HSS) or oscillatory shear stress (OSS) for 1 and 3 days. Arginase I and II expression, cellular localization and enzyme activity were, respectively, assessed by Western blot, immunohistochemistry and colorimetric determination of urea. The contribution of arginase to the processes of endothelial dysfunction, cell proliferation and arterial remodeling induced by OSS was evaluated by administration of the arginase inhibitor N-omega-hydroxy-nor-l-arginine (nor-Noha).


RESULTS
Only arginase II isoform was detected on porcine carotid endothelial cells and on carotid artery. Exposure of arteries to OSS increased arginase II expression and activity as compared to HSS. Inhibition of arginase by nor-Noha improved NO-dependent endothelial function and decreased total vascular ROS formation in arteries submitted to OSS. In addition, inhibition of arginase activity decreased smooth muscle cell proliferation rate with no effect on collagen content after OSS.


CONCLUSIONS
Exposure of carotid artery to oscillatory flow induced a more pronounced activation of arginase as compared to HSS. Inhibition of arginase in arteries exposed to OSS improved NO-dependent endothelial function and decrease smooth muscle cell proliferation rate, both processes are important for the focal development of atherosclerotic plaque.
Thacher
Tyler N
TN
Swiss Federal Institute of Technology Lausanne, 1015 Lausanne, Switzerland.
Gambillara
Veronica
V
Riche
Fabienne
F
Silacci
Paolo
P
Stergiopulos
Nikos
N
da Silva
Rafaela F
RF
D000818:Animals; D001119:Arginase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050197:Atherosclerosis / Q000201:enzymology* / Q000503:physiopathology*; D015153:Blotting, Western; D002339:Carotid Arteries / Q000201:enzymology / Q000503:physiopathology; D003124:Colorimetry; D004730:Endothelium, Vascular / Q000201:enzymology / Q000503:physiopathology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D053858:Metabolic Networks and Pathways; D020033:Protein Isoforms / Q000032:analysis; D013314:Stress, Mechanical; D013552:Swine
D020033:Protein Isoforms; D001119:Arginase