Arginase and the Aging Cardiovascular System

精氨酸酶与衰老的心血管系统

• 批准号: 6786605
• 负责人: DAN E BERKOWITZ
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6786605
• 关键词: aging; animal old age; arginase; arginine; biological signal transduction; cardiovascular pharmacology; cardiovascular system; enzyme activity; enzyme inhibitors; enzyme mechanism; free radicals; gene expression; laboratory rat; mature animal; nitric oxide; nitric oxide synthase; vascular endothelium; vascular resistance; vasodilation

DESCRIPTION (provided by applicant): Abnormal endothelial NO vasodilator mechanisms contribute to increased cardiovascular risk in the aging cardiovascular system. L-arginine, the NO synthase substrate, improves endothelial dependent vasodilatation by unknown mechanism(s), since intracellular concentrations of L-arginine far exceed the Kd for nitric oxide synthase (NOS). The observation that L-arginine administration increases NO synthesis and enhances endothelial function even in the setting of apparently adequate L-arginine levels in the cell has come to be called the "L-arginine paradox". Arginase, an enzyme of the urea cycle also uses L-arginine as a substrate and is present in cardiovascular tissue. Our preliminary data demonstrate that the L-arginine metabolizing enzyme, arginase, reciprocally regulates vascular endothelial NOS activity, and directly influences vascular relaxation in rats. Furthermore, arginase activity and expression are increased in agingrat vessels, and arginase inhibition attenuates the increased reactive oxygen species (ROS) produced in old rat vascular tissue. We hypothesize that: 1) endothelial arginase limits endothelial NO production and thus, endothelial-dependent vasodilatation, by competing for intracellular L-arginine; 2) vascular endothelial dysfunction of aging is associated with increased expression of endothelial arginase, and inhibition of arginase restores NO-dependent signaling and endothelial function to that of the young phenotype; 3) relative substrate (L-arginine) deficiency enhances ROS production further compromising endothelial function by altering the balance between NO and 02-; and 4) chronic arginase inhibition will restore Larginine reponsiveness, enhance NO signaling, and decrease ROS production thereby restoring altered integrated cardiovascular parameters (increased vascular and ventricular stiffness and altered ventriculararterial coupling) to that of the young phenotype. We will study the regulatory role of arginase in normal endothelial function and NO signaling, as well as its role in the pathophysiology of endothelial dysfunction associated with aging. These experiments will offer novel insights into regulation of the NO signaling pathway, and the balance between NO and 02- in endothelial function, with important therapeutic implications for a wide variety of disorders characterized by endothelial dysfunction.

描述（由申请人提供）：异常的内皮一氧化氮血管舒张机制会导致衰老心血管系统的心血管风险增加。 L-精氨酸，NO 合酶底物，通过未知机制改善内皮依赖性血管舒张，因为细胞内 L-精氨酸浓度远远超过一氧化氮合酶 (NOS) 的 Kd。即使在细胞中明显足够的 L-精氨酸水平的情况下，L-精氨酸施用也会增加 NO 合成并增强内皮功能，这一观察结果被称为“L-精氨酸悖论”。精氨酸酶是尿素循环的一种酶，也使用 L-精氨酸作为底物，存在于心血管组织中。我们的初步数据表明，L-精氨酸代谢酶精氨酸酶可相互调节血管内皮 NOS 活性，并直接影响大鼠的血管舒张。此外，衰老大鼠血管中的精氨酸酶活性和表达增加，并且精氨酸酶抑制减弱了老年大鼠血管组织中产生的活性氧（ROS）的增加。我们假设：1）内皮精氨酸酶通过竞争细胞内的 L-精氨酸来限制内皮 NO 的产生，从而限制内皮依赖性血管舒张； 2) 衰老的血管内皮功能障碍与内皮精氨酸酶表达增加有关，抑制精氨酸酶可使NO依赖性信号传导和内皮功能恢复到年轻表型的水平； 3) 相对底物（L-精氨酸）缺乏会增强 ROS 的产生，通过改变 NO 和 02- 之间的平衡进一步损害内皮功能； 4) 长期精氨酸酶抑制将恢复精氨酸反应性，增强 NO 信号传导，并减少 ROS 产生，从而将改变的综合心血管参数（血管和心室硬度增加以及心室动脉耦合改变）恢复到年轻表型的水平。我们将研究精氨酸酶在正常内皮功能和 NO 信号传导中的调节作用，及其在与衰老相关的内皮功能障碍的病理生理学中的作用。这些实验将为NO信号通路的调节以及内皮功能中NO和O2-之间的平衡提供新的见解，对以内皮功能障碍为特征的多种疾病具有重要的治疗意义。