Vascular specific ACE expression and atherosclerosis

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It is now well established that the renin angiotensin system is causally involved in the pathogenesis of atherosclerosis. Data from clinical trails clearly demonstrate that angiotensin converting enzyme inhibitors decrease cardiovascular morbidity and mortality in patients at increased risk for cardiovascular disease. Data from our laboratory and others show that chronic infusion of angiotensin II dramatically accelerates atherosclerosis in apoE deficient mice. Similarly, interference with the renin angiotensin system prevents the development of atherosclerosis in both murine and rabbit models of atherosclerosis. Thus, there are compelling data linking angiotensin II to the initiation and progression of atherosclerosis. There is a growing appreciation that the systemic renin angiotensin II system may not be as important to vascular wall pathology as local production of angiotensin II within the arterial wall. Indeed, many of the components of the renin angiotensin II system are expressed in the cell types that comprise the vessel wall. This expression is not uniform as expression of a given component may be cell specific. In particular, ACE was traditionally thought to be expressed primarily in the lung. More recently, vascular endothelial cells and macrophages have been shown to be the primary sources of ACE within the arterial wall. Our own preliminary data suggest that in the DOCA/salt model of hypertension, systemic levels of angiotensin/I are low whereas the local generation of angiotensin II within the arterial wall is increased. However, despite the extensive study of vascular ACE activity and subsequent Angiotensin II production, the functional importance of tissue-specific ACE expression remains somewhat unclear. Thus, it is the overall goal of this proposal to rigorously test the hypothesis that vascular ACE expression is critically involved in the pathogenesis of atherosclerosis. Furthermore, we will utilize unique genetic models of ACE expression to specifically examine the functional importance of endothelial and macrophage cell-specific expression of ACE in this process.