Arginase and Nitric Oxide in Atherosclerosis

动脉粥样硬化中的精氨酸酶和一氧化氮

• 批准号: 6697306
• 负责人: LOUIS J IGNARRO
• 金额: $ 34.89万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-06 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6697306
• 关键词: arginase; arginine; atherosclerosis; cell proliferation; enzyme activity; enzyme induction /repression; laboratory rabbit; nitric oxide; nitrogen metabolism; pathologic process; polyamines

DESCRIPTION (Verbatim from the application): In the response-to-injury hypothesis of atherosclerosis, numerous factors are involved in atherosclerotic lesions resulting from local injury, including impairment of the arginine-NO pathway. NO and its precursor intermediate, N-hydroxyarginine (NOHA), are potent inhibitors of cell proliferation that interfere with the arginine-polyamine pathway. Deficient production of NOHA + NO may accelerate proliferation of vascular smooth muscle, macrophages and other cells. Arginase is a high turnover enzyme that utilizes arginine to form ornithine + urea. Ornithine is a precursor for polyamines required for cell growth. Elevated arginase activity causes increased conversion of arginine to polyamines at the expense of decreased conversion of arginine to NOHA + NO due to limiting arginine availability. Decreased production of NOHA + NO further amplifies polyamine production due to decreased negative feedback on the arginine-polyamine pathway. Increased arginase expression is characteristic of atherosclerotic lesions and administration of arginase inhibitors to animals with atherosclerosis decreases disease progression. The central hypothesis that drives this proposal is that atherosclerosis is associated with the induction of arginase, leading to increased polyamine production that is further enhanced by diminished production 01 NOHA + NO. The principal objective of the proposed research is to determine whether the increased cell proliferation in atherosclerosis is attributed to increased arginase activity and consequent increased polyamine production coupled to decreased NOHA and NO production. The rationale for this objective is based on our previous findings that NOHA and NO inhibit cell growth by interfering with two sequential steps in the arginine-polyamine pathway. Two specific aims are proposed to address the objective: (a) to elucidate the mechanisms by which increased arginase activity leads to increased cell proliferation, and (b) to determine the effectiveness and mechanisms by which arginase inhibitors slow the progression of atherosclerosis in animal models of atherosclerosis. The feasibility of this approach is borne out by the extensive preliminary data that support the central hypothesis.

描述(来自应用程序的逐字)：在伤害反应中 动脉粥样硬化假说，动脉粥样硬化涉及多种因素 局部损伤引起的损害，包括精氨酸-NO的损害 路径。NO及其前体中间体N-羟基精氨酸(NOHA) 有效的细胞增殖抑制因子，干扰 精氨酸-多胺途径。NOHA+NO的生产不足可能加速 血管平滑肌、巨噬细胞等细胞增殖。精氨酸酶 是一种利用精氨酸形成鸟氨酸+尿素的高周转酶。 鸟氨酸是细胞生长所需的多胺的前体。高架 精氨酸酶活性导致精氨酸转化为多胺的增加 由于限制，精氨酸转化为NOHA+NO减少的费用 精氨酸可利用性。NoHA+NO产量减少进一步放大 多胺生产，因为对 精氨酸-多胺途径。精氨酸酶表达增加是 动物动脉粥样硬化病变和精氨酸酶抑制剂的应用 动脉粥样硬化可以减少疾病的进展。核心假设是 推动这一提议的是动脉粥样硬化与诱导 精氨酸酶，导致多胺产量增加，从而进一步增强 减产01 Noha+No.建议的主要目标是 研究是为了确定细胞增殖增加是否在 动脉粥样硬化归因于精氨酸酶活性的增加和随之而来的 多胺产量增加，同时NOHA和NO产量减少。这个 这一目标的理论基础是基于我们之前的发现，即Noha和No 通过干扰细胞中的两个连续步骤来抑制细胞生长 精氨酸-多胺途径。提出了两个具体目标来解决 目的：(A)阐明精氨酸酶活性升高的机制 导致细胞增殖增加，以及(B)确定其有效性 以及精氨酸酶抑制剂延缓血管病变进展的机制 动脉粥样硬化动物模型中的动脉粥样硬化。这样做的可行性 广泛的初步数据证明了这种方法，这些数据支持 中心假说。