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: 6316119
• 负责人: LOUIS J IGNARRO
• 金额: $ 42.97万
• 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 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6316119
• 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记录）：在对损伤的反应中 动脉粥样硬化假说认为，动脉粥样硬化的发生与多种因素有关， 由局部损伤引起的病变，包括精氨酸-NO的损伤 通路NO及其前体中间体N-羟基精氨酸（NOHA）， 有效的细胞增殖抑制剂， 精氨酸-多胺途径NOHA + NO的生产不足可能会加速 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。升高 精氨酸酶活性导致精氨酸向多胺的转化增加， 由于限制精氨酸向NOHA + NO的转化而降低的费用 精氨酸利用率。NOHA + NO的产生减少进一步放大了 多胺生产由于减少负反馈的 精氨酸-多胺途径表达增加是 动脉粥样硬化损伤和对动物施用抗动脉粥样硬化酶抑制剂 与动脉粥样硬化的关系会减少疾病的进展。核心假设是， 驱动这一提议的是动脉粥样硬化与诱导 的酶，导致增加的多胺生产，这是进一步增强 通过减少生产01 NOHA + NO。拟议的主要目标 研究是为了确定是否增加细胞增殖， 动脉粥样硬化归因于凝血酶活性增加， 增加的多胺产生与降低的NOHA和NO产生相关联。的 这一目标的基本原理是基于我们以前的发现，NOHA和NO 通过干扰细胞生长过程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，以解决 目的：（a）阐明增加酶活性的机制， 导致细胞增殖增加，和（B）确定有效性 以及酶抑制剂减缓肿瘤进展的机制 动脉硬化动物模型中的动脉硬化。的可行性 这种方法得到了广泛的初步数据的证实， 中心假设