Role of Arginase Pathway in Response to Shear Stress: New Potential Therapeutic Targets for Atherosclerosis?

Abstract

Introduction: 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. However, the role of arginase pathway in response to shear stress has never been investigated. Methods: To evaluate the regulation of arginases by different shear stress patterns without neuroendocrine factors, we perfused carotid arterial segments to the following hemodynamic conditions: unidirectional high and low shear stress, and oscillatory shear stress. After 3 days of flow exposure, vascular function was analyzed by diameter measurements, arginase expression and localization by western blot and immunohistochemistry, respectively. We compared these well-controlled measurements to an in vivo model of shear stress-induced atherogenesis. In brief, the carotid artery of ApoE-/- mice, fed with high cholesterol diet, was exposed to high, low and oscillatory shear stress values by the placement of a shear stress modifier for 9 weeks. Immunohistochemistry was used to determine the expression of arginase I and II and to characterize the arginase expression in different cell types encountered in atherosclerotic plaques. Results: Our preliminary results from ex vivo perfusion arteries showed for the first time that exposure of carotid segments to high shear stress conditions (athero-protective) significantly decrease arginase II protein expression as compared to both low and oscillatory flow conditions. Immunohistochemisty analysis confirmed a pronounced decrease in the expression of arginase II on ECs and SMCs exposed to this high shear stress. Our preliminary data suggest that arginase I and II are also regulated by shear stress in vivo. Arginases were up-regulated on EC, SMC and macrophages of carotid segments exposed either to low stress or to oscillatory shear stress conditions. Conclusions: The present study demonstrates that arginase expression is already modulated by 3 days exposure to different shear stress patterns in carotid arteries perfused ex vivo. Similar findings are also observed in a model of shear stress-induced atherogenesis in vivo. Histopathological analysis of carotid lesions in ApoE-/- mice exposed to shear stress and chronically treated with arginase inhibitors may further elucidate the role of arginases in modulating both plaque size and vulnerability