VASCULAR MECHANISMS IN ATHEROGENESIS

内皮功能受损是实验动物和人类动脉粥样硬化的标志，可能有助于动脉粥样硬化及其并发症的发展。本项目的总体主题是动脉粥样硬化形成中内皮和血管肌肉功能障碍的机制。研究人员建议综合生理和分子方法来研究危险因素和氧化剂可能产生动脉粥样硬化的机制。该方案包括三个项目和一个行政核心。项目1检验了血管紧张素II导致血管中超氧化物水平增加的假设，该机制可能导致高血压加速动脉粥样硬化。两个新的高血压转基因小鼠已被用来测试这一假设。一种模型中血管紧张素II的循环水平显著升高，而另一种模型中血管紧张素II的循环水平正常;然而，两种模型中的高血压程度相似。这些模型将允许一种新的方法来检查血管紧张素在高血压和动脉粥样硬化的血管变化中的作用。项目2的研究人员最近报告称，与之前关注内皮产生的活性氧（ROS）作用的研究相反，血管肌肉是动脉粥样硬化血管中超氧化物的主要来源。研究提出，以确定的重要性，并检查酶的机制，占，生产超氧化物的平滑肌动脉粥样硬化血管。研究提出，以确定的重要性，并检查酶的机制，占，生产超氧化物平滑肌动脉粥样硬化血管。研究计划在小鼠动脉粥样硬化的遗传模型中进行，并在动脉粥样硬化和抑制的灵长类动物模型中进行。项目3提出了一个假设，即ROS的过度产生可能会调节平滑肌细胞的增殖和促进平滑肌细胞的死亡。基因转移方法将用于直接增加抗氧化酶的浓度，而不是使用酶的局部应用，研究计划确定内源性H2 O2以及超氧化物和H2 O2之间的平衡是否调节平滑肌细胞的增殖和活力。这些研究将检查导致新生内膜平滑肌细胞对RO 2细胞毒性敏感性增强的机制。该计划的目标包括：澄清危险因素产生动脉粥样硬化的机制，深入了解动脉粥样硬化血管中活性氧的细胞和酶源，以及更好地了解潜在的治疗靶点，包括氧化过程，血管紧张素II和高脂血症。

Impairment of endothelial function, which is a hallmark of atherosclerosis in experimental animal and humans, may contribute to development of atherosclerosis and its complications. The overall theme of this Program is mechanisms of dysfunction of endothelium and vascular muscle in atherogenesis. The investigators propose to integrated physiological and molecular approaches to examine mechanisms by which risk factors and oxidants may produce atherosclerosis. The Program consists of three projects and an administrative core. Project 1 tests the hypothesis that angiotensin II contributes to increased levels of superoxide in blood vessels and that this mechanism may contribute to acceleration of atherosclerosis by hypertension. Two novel hypertensive transgenic mice have been made to test this hypothesis. Circulating levels of angiotensin II are markedly elevated in one model, and normal in the other model; the degree of hypertension, however, is similar in the two models. These models will allow a new approach to examine the role of angiotensin in vascular changes during hypertension and atherosclerosis. The investigators in Project 2 have reported recently that, in contrast to previous studies which have focused on the role of reactive oxygen species (ROS) generated by endothelium, vascular muscle is a major source of superoxide in atherosclerotic vessels. Studies are proposed to determine the important of, and examine enzymatic mechanisms that account for, production of superoxide by smooth muscle in atherosclerotic vessels. Studies are proposed to determine the importance of, and examine enzymatic mechanisms that account for, production of superoxide smooth muscle in atherosclerotic vessels. Studies are planned in a genetic model of atherosclerosis in mice, and in a primate model of atherosclerosis and repression. Project 3 proposes to test the hypothesis that excessive production of ROS may regulate both proliferation and promote death of smooth muscle cells. Gene transfer approaches will be used to directly increase concentration of antioxidant enzymes, rather than using topical application of the enzymes, Studies are planned to determine whether endogenous H2O2, and the balance between superoxide and H2O2, regulate both proliferation and viability of smooth muscle cells. The studies will examine mechanisms that account for enhanced susceptibility of neointimal smooth muscle cells to cytotoxicity by RO2. Target goals of the Program include clarification include clarification of mechanisms by which risk factors produce atherosclerosis, insight into cellular and enzymatic sources of reactive oxygen species in atherosclerotic vessels, and better understanding of potential therapeutic targets, including oxidative processes, angiotensin II, and hyperlipidemia.