Atherosclerosis in hypertension: Role of angiotensin II

该项目的总体目标是研究血管紧张素II在高血压和动脉粥样硬化期间促进血管功能障碍的机制。尽管血管紧张素II在高血压中的作用一直是一个活跃的研究领域，但拟议的研究将采用一种新的方法来解决血管紧张素II在动脉粥样硬化期间导致血管功能障碍的假设。为这些研究已经产生了两种新的小鼠模型——一种是系统地过度表达人肾素和血管紧张素原基因的转基因小鼠（系统模型，T+/ a +），另一种是过度表达相同的两个基因的小鼠，但血管紧张素原的表达被肾脏特异性启动子的使用限制在肾脏（肾脏特异性模型，R+/K+）。研究设计的一个关键方面是发现血管紧张素II循环水平在全身模型中显著升高，但在肾脏特异性模型中是正常的。尽管肾特异性模型的血浆血管紧张素II水平正常，但两种模型的高血压程度相似。这种方法可以直接检测人肾素、血管紧张素原和循环血管紧张素II在高血压和动脉粥样硬化模型中的作用。研究的一个目标是检验高血压小鼠体内超氧化物水平升高和血管功能障碍的假设。由于血管紧张素II循环水平仅在全身性模型中升高，我们预计全身性模型中的血管异常将比肾特异性模型中的血管异常更大。研究的第二个目标将是检验高血压患者在动脉粥样硬化期间的超氧化物和血管功能障碍水平高于动脉粥样硬化或高血压患者的假设。更重要的是，提出的实验将检验这样一个假设，即在存在高胆固醇血症的情况下，系统模型中的功能异常和动脉粥样硬化程度将比肾脏特异性模型更严重。为了研究动脉粥样硬化，双转基因小鼠将与载脂蛋白e缺陷小鼠杂交。这一建议的一个优势是使用新的小鼠模型来表征导致血管超氧化物产生和异常功能的系统。除了对主动脉的研究外，还将研究小鼠动脉粥样硬化病变的主要形成部位，冠状动脉和脑动脉。在肾素-血管紧张素系统中产生选择性改变的能力，然后检查血管壁的变化，将为研究血管紧张素II在高血压和动脉粥样硬化中的作用提供新的方法。

The overall objective of this project is to examine mechanisms by which angiotensin II contributes to vascular dysfunction during hypertension and atherosclerosis. Although the role of angiotensin II in hypertension has been an active area of investigation, the proposed studies will use a novel approach to address the hypothesis that angiotensin II contribute to vascular dysfunction during atherosclerosis. Two new murine models have been produced for these studies- a transgenic mouse that systemically over-expresses human renin and angiotensinogen genes (the systemic model, T+/A+), and a second mouse which over-expresses the same two genes, but expression of angiotensinogen has been restricted to the kidney by the use of a kidney-specific promoter (renal-specific model, R+/K+). A key aspect in the design of the proposed studies relates to the finding that circulating levels of angiotensin II are markedly elevated in the systemic model, but are normal in the renal-specific model. Despite normal levels of plasma angiotensin II in the renal-specific model, the degree of hypertension is similar in the two models. This approach allows the direct examination of the role of human renin and angiotensinogen and circulating angiotensin II in models of hypertension and atherosclerosis. One goal of the studies will be to examine the hypothesis that levels of superoxide are increased and vascular dysfunction is present in hypertensive mice. Because circulating levels of angiotensin II are elevated only in the systemic model, we anticipate that vascular abnormalities will be is greater in the systemic model than in the renal- specific model. A second goal of the studies will be to examine the hypothesis that levels of superoxide and vascular dysfunction during atherosclerosis in the presence of hypertension is greater than during atherosclerosis or hypertension alone. More importantly, proposed experiments will examine the hypothesis that in the presence of hypercholesterolemia, functional abnormalities and the extent of atherosclerosis will be more severe in the systemic model than in the renal-specific model. For studies of atherosclerosis, double transgenic mice will be crossed with apolipoprotein E-deficient mice. A strength of this proposal is the use of novel murine models to characterize systems which contribute to superoxide production and abnormal function in blood vessels. In addition to studies of aorta, a major site of formation of atherosclerotic lesions, coronary and cerebral arteries from mice will also be studied The ability to produce selective alterations in the renin- angiotensin system and then to examine resulting changes in the vascular wall will allow a new approach to examine the role of angiotensin II during hypertension and atherosclerosis.