Vascular specific ACE expression and atherosclerosis

现已证实肾素-血管紧张素系统与动脉粥样硬化的发病密切相关。来自临床试验的数据清楚地表明，血管紧张素转换酶抑制剂可以降低心血管疾病风险增加的患者的心血管发病率和死亡率。来自我们实验室和其他实验室的数据显示，长期输注血管紧张素II会显著加速载脂蛋白E缺陷小鼠的动脉粥样硬化。同样，对肾素血管紧张素系统的干扰可以防止动脉粥样硬化在小鼠和兔模型中的发展。因此，有令人信服的 将血管紧张素II与动脉粥样硬化的发生和发展联系起来的数据。越来越多的人认识到，系统性肾素血管紧张素系统可能不像 血管壁病理：动脉壁局部产生血管紧张素II。事实上，肾素血管紧张素II系统的许多成分都在构成血管壁的细胞类型中表达。这种表达是不统一的，因为给定成分的表达可能是细胞特异性的。特别是，血管紧张素转换酶传统上被认为主要在肺中表达。最近，血管内皮细胞和巨噬细胞被证明是动脉壁内血管紧张素转换酶的主要来源。我们自己的初步数据表明，在DOCA/SALT高血压模型中，全身血管紧张素/I水平较低，而 动脉壁内血管紧张素II的局部生成增加。然而，尽管对血管ACE活性和随后的血管紧张素II的产生进行了广泛的研究，但组织特异性ACE表达的功能重要性仍然有些不清楚。因此，这项建议的总体目标是严格检验血管ACE表达在动脉粥样硬化发病机制中的关键作用这一假设。此外，我们将利用ACE表达的独特遗传模型来具体研究血管内皮细胞和巨噬细胞特异性表达的ACE在这一过程中的功能重要性。

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.