Atherosclerosis in hypertension: Role of angiotensin II

本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过程中导致血管功能障碍的机制。虽然血管紧张素II在高血压中的作用一直是一个活跃的研究领域，但拟议的研究将使用一种新的方法来解决血管紧张素II导致动脉粥样硬化期间血管功能障碍的假设。已经为这些研究产生了两种新的鼠模型-一种全身性过表达人肾素和血管紧张素原基因的转基因小鼠（全身性模型，T +/A+），和另一种过表达相同的两种基因的小鼠，但是通过使用肾特异性启动子，血管紧张素原的表达被限制在肾脏（肾特异性模型，R +/K+）。拟定研究设计中的一个关键方面涉及发现血管紧张素II的循环水平在全身模型中显著升高，但在肾脏特异性模型中正常。尽管在肾脏特异性模型中血浆血管紧张素II水平正常，但两种模型中的高血压程度相似。这种方法允许直接检查人的肾素和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中超氧化物水平增加和血管功能障碍存在的假设。因为血管紧张素II的循环水平仅在全身模型中升高，我们预期全身模型中的血管异常将大于肾特异性模型中的血管异常。研究的第二个目标是检验这样一个假设，即在高血压存在下动脉粥样硬化期间超氧化物和血管功能障碍的水平大于动脉粥样硬化或单独高血压期间。更重要的是，拟议的实验将检查的假设，即在高胆固醇血症的存在下，功能异常和动脉粥样硬化的程度将是更严重的系统模型比肾脏特异性模型。对于动脉粥样硬化的研究，双转基因小鼠将与载脂蛋白E缺陷小鼠杂交。该建议的一个优点是使用新的小鼠模型来表征有助于超氧化物产生和血管功能异常的系统。除了研究主动脉，形成动脉粥样硬化病变，冠状动脉和脑动脉的主要网站从小鼠也将进行研究的能力，产生选择性改变的肾素-血管紧张素系统，然后检查所产生的变化，在血管壁将允许一个新的方法来检查血管紧张素II在高血压和动脉粥样硬化的作用。

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.