P.096 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.

Methods

To evaluate the regulation of arginases by different shear stress patterns without neuroendocrine factors, we perfused carotid arterial segments to unidirectional high and low shear stress, and oscillatory shear stress. After 3 days of flow exposure, vascular function, arginase expression and localization were analyzed. 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 similar hemodynamic conditions by the placement of a shear stress modifier for 9 weeks.

Results

Our results 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 expression of arginase II on SMCs and macrophages on in the atherosclerotic plaques formed by oscillatory and low shear stress in vivo.

Conclusions

The present study demonstrates that arginase expression is modulated by 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.