ARGINASE AND ARTERIAL INJURY

精氨酸酶和动脉损伤

• 批准号: 6926566
• 负责人: WILLIAM DURANTE
• 金额: $ 36.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2005-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926566
• 关键词: AP1 protein; RNase protection assay; angiogenesis; arginase; blood vessel disorder; cell growth regulation; cell migration; collagen; enzyme activity; enzyme induction /repression; gel mobility shift assay; gene expression; growth factor; homocystinuria; laboratory mouse; laboratory rat; nitric oxide; protein metabolism; scintillation counter; thin layer chromatography; tissue /cell culture; transfection; vascular smooth muscle; western blottings

DESCRIPTION (provided by applicant): The broad long-term objective of this research proposal is to establish arginase I as a novel regulator of vascular function. We have discovered that vascular smooth muscle cells (SMC) express arginase I and that vascular mitogens and atherogenic factors found at sites of vascular injury stimulate arginase I gene expression. The central hypothesis of this proposal is that arginase I is a critical regulator of the SMC response to vascular injury. To test our hypothesis, we plan to pursue the following 3 complementary and linked specific aims. In aim 1, the effect of arginase on vascular SMC proliferation, migration, collagen and nitric oxide (NO) synthesis will be investigated. If arginase I stimulates SMC growth, migration, or collagen synthesis we will determine whether polyamines or L-proline mediate these actions. In addition, the effect of arginase I on cell cycle proteins will be explored. In contrast, if arginase I inhibits inflammatory cytokine-mediated NO production we will examine if this is mediated via the depletion of intracellular L-arginine. We will also determine if the inhibition of NO formation by arginase I prevents SMC apoptosis. In aim 2, the regulation and role of arginase I on the response to arterial injury will be investigated. These studies will examine the expression of arginase I as well as the production of polyamines, L-proline, and NO using the rat carotid artery injury model. We will also determine whether inhibition of arginase I activity using pharmacological and antisense approaches attenuates the remodeling response following arterial injury. Alternatively, we will examine whether arginase I gene transfer to the vessel wall exacerbates the remodeling response. In addition, we will generate mice with homozygous arginase I inactivation targeted specifically to vascular SMC and determine whether this influences the remodeling response. In aim 3, the regulation and role of arginase I in hyperhomocysteinemia will be investigated using cultured SMC and genetic and dietary animal models of hyperhomocysteinemia. It is anticipated that this project will (a) establish arginase I as a novel regulator of the vessel wall's response to injury and (b) implicate the arginase I enzyme as a promising new therapeutic target in treating atheroproliferative disorders of the vessel wall.

描述（由申请人提供）：这项研究建议的广泛长期目标是将精氨酸酶I建立为血管功能的新调节剂。我们发现血管平滑肌细胞（SMC）表达精氨酸酶I，以及在血管损伤部位发现的血管有丝分裂因子和动脉粥样硬化因子刺激精氨酸酶I基因表达。该提议的中心假设是精氨酸酶I是SMC对血管损伤反应的关键调节剂。为了检验我们的假设，我们计划追求以下3个互补和链接的特定目标。在AIM 1中，将研究精氨酸酶对血管SMC增殖，迁移，胶原蛋白和一氧化氮（NO）合成的影响。如果精氨酸酶I刺激SMC的生长，迁移或胶原蛋白合成，我们将确定多胺或L-聚氨会是否介导这些作用。另外，将探讨精氨酸I对细胞周期蛋白的影响。相反，如果精氨酸酶I抑制炎性细胞因子介导的无产生，我们将检查是否通过细胞内L-精氨酸的耗竭来介导。我们还将确定精氨酸酶I对NO形成的抑制是否可以防止SMC凋亡。在AIM 2中，将研究精氨酸酶I对动脉损伤反应的调节和作用。这些研究将研究精氨酸酶I的表达以及使用大鼠颈动脉损伤模型的多胺，L-聚胺的产生。我们还将确定使用药理学和反义方法抑制精氨酸酶I活性是否会减轻动脉损伤后的重塑反应。或者，我们将检查精氨酸酶I基因转移到血管壁是否会加剧重塑反应。此外，我们将生成具有专门针对血管SMC的纯合精氨酸酶I的小鼠，并确定这是否影响重塑反应。在AIM 3中，将使用培养的SMC以及高脑结构血症的遗传和饮食动物模型来研究精氨酸酶I在高层植型血症中的调节和作用。预计该项目将（a）建立精氨酸酶I作为血管壁对损伤反应的新型调节剂，并且（b）将精氨酸酶I酶视为一种有希望的新的治疗靶标，以治疗血管壁的动脉粥样硬化疾病。