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（逐字从应用程序中）：在对伤害的响应中 动脉粥样硬化的假设，动脉粥样硬化涉及许多因素 局部损伤引起的病变，包括精氨酸 - 不损害 路径。否及其前体中间体N-羟基氨基氨酸（NOHA）为 有效的细胞增殖抑制剂 精氨酸聚胺途径。 NOHA + NO HO的产生不足可能会加速 血管平滑肌，巨噬细胞和其他细胞的增殖。精氨酸酶 是一种使用精氨酸形成鸟氨酸 +尿素的高离职酶。 鸟氨酸是细胞生长所需的多胺的前体。高架 精氨酸酶活性会导致精氨酸转化为多胺在 由于限制，精氨酸转化为NOHA + NO的费用 精氨酸的可用性。 Noha +的生产减少，没有进一步的放大 由于负面反馈的减少，多胺产生 精氨酸聚胺途径。精氨酸酶表达增加是 动脉粥样硬化病变和精氨酸酶抑制剂对动物 动脉粥样硬化会降低疾病的进展。中心假设是 驱动该提议是动脉粥样硬化与诱导有关 精氨酸酶，导致多胺产生增加，进一步增强 通过减少生产01 NOHA + NO。拟议的主要目标 研究是确定细胞增殖是否增加 动脉粥样硬化归因于精氨酸酶活性的增加，因此 多胺产量增加，加为NOHA且无生产。这 这个目标的理由是基于我们以前的发现，Noha和No 通过干扰两个顺序步骤来抑制细胞的生长 精氨酸聚胺途径。提出了两个具体目标来解决 目的：（a）阐明精氨酸活性增加的机制 导致细胞增殖增加，（b）确定有效性 和精氨酸酶抑制剂减慢进展的机制 动脉粥样硬化动物模型中的动脉粥样硬化。此的可行性 通过支持该方法的广泛初步数据证明了方法 中央假设。