L-ARGININE METABOLISM AND CORONARY VASCULAR FUNCTION

L-精氨酸代谢和冠状血管功能

• 批准号: 2029679
• 负责人: LIH KUO
• 金额: $ 22.46万
• 依托单位: TEXAS ENGINEERING EXPERIMENT STATION
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2029679
• 关键词: aminoacid metabolism; aminoacid transport; arginine; atherosclerosis; coronary vessels; low density lipoprotein; nitric oxide; pathologic process; swine; tissue /cell culture; vascular endothelium

Atherogenesis is a complex process that appears to be initiated by alterations of endothelium. An elevated level of plasma low-density lipoproteins (LDL) is thought to be responsible for the development of atherosclerosis because the characteristics of LDL-induced endothelium dysfunction are very similar to those observed in hypercholesterolemic and atherosclerotic subjects. Indeed, exposure of normal large coronary arteries to pathological concentrations of LDL inhibits endothelium- dependent vasorelaxation within minutes. However, it is unclear whether coronary microvessels (<150 MU m) are also susceptible to LDL. This issue is important because these microvessels not only contribute over 70% of coronary resistance but also play a major role in the regulation of coronary blood flow. Interestingly, many studies have shown that administration of a high dose of L-arginine normalizes atherosclerosis- and LDL-induced vascular dysfunction. Since L-arginine is a biological precursor for nitric oxide (NO) synthesis, these results may suggest that the observed vascular dysfunction is due to the impairment of NO synthesis and/or release during LDL exposure. However, the underlying mechanism responsible for this impairment has not been identified, especially at the microcirculatory level. In addition, the mechanism of restoring vascular function by L-arginine is also unclear. Therefore, it is hypothesized in this proposal that the elevated LDL, especially oxidized LDL, alters L- arginine transport and/or L-arginine/NO metabolism in the endothelium and thus leads to vascular dysfunction due to the impairment of NO synthesis and/or release. To test this hypothesis, the experiments are designed: I) to demonstrate conclusively that the deficiency in endothelial release of NO during LDL exposure is responsible for the vascular dysfunction, 2) to determine the alterations of L-arginine transport and metabolism toward the synthesis of NO during LDL exposure, and 3) to delineate the mechanism(s) of restoring vascular function by the administration of L-arginine. To achieve these goals, we will use both isolated arterioles (<150 MU m) and cultured endothelial cells from the porcine coronary microcirculation as experimental models. The isolated arterioles will be cannulated and pressurized for functional study. The cultured cells will be used to probe the mechanism of alteration of L-arginine/NO metabolism. The intact vessel and cultured cell studies will complement each other to address the relationship between vascular function and endothelial L-arginine/NO metabolism during exposure to atherogenic agents. Results from these studies will provide valuable information toward our understanding of the mechanism of vascular dysfunction during the development of atherosclerosis. In addition, elucidation of anti-atherogenic effect of L- arginine may provide a foundation for future therapeutic manipulation of vascular function during hypercholesterolemia and/or atherosclerosis.

动脉粥样硬化的发生是一个复杂的过程，似乎是由 内皮细胞的改变。血浆低密度水平升高 脂蛋白(LDL)被认为是导致 动脉粥样硬化是因为低密度脂蛋白诱导的内皮细胞的特性 功能障碍与高胆固醇血症和 动脉粥样硬化受试者。事实上，暴露于正常的大冠状动脉 动脉对病理浓度的低密度脂蛋白抑制内皮- 依赖的血管松弛在几分钟内。然而，目前还不清楚是否 冠状动脉微血管(&lt；150微米)也易受低密度脂蛋白的影响。这一期 很重要，因为这些微血管不仅贡献了超过70%的 冠脉阻力也在调节心肌梗死中发挥重要作用。 冠脉血流量。有趣的是，许多研究表明 服用大剂量L精氨酸可使动脉粥样硬化正常化 低密度脂蛋白引起的血管功能障碍。由于L-精氨酸是一种生物 一氧化氮(NO)合成的前体，这些结果可能表明 观察到的血管功能障碍是由于一氧化氮合成的障碍。 和/或在低密度脂蛋白暴露期间释放。然而，潜在的机制 对这种损害负有责任的人尚未确定，特别是在 微循环水平。此外，血管修复的机制 L的作用--精氨酸也不清楚。因此，它被假设为 这一关于升高的低密度脂蛋白，特别是氧化低密度脂蛋白改变L的说法-- 血管内皮细胞的精氨酸转运和/或L-精氨酸/一氧化氮代谢 从而导致由于NO合成障碍而导致的血管功能障碍 和/或释放。为了验证这一假设，设计了以下实验：i) 最终证明血管内皮细胞释放的缺陷 在低密度脂蛋白暴露期间，NO是导致血管功能障碍的原因，2)到 测定L-精氨酸转运和代谢的变化 低密度脂蛋白暴露过程中NO的合成，以及3)阐明其机制(S) 应用L精氨酸恢复血管功能的研究。至 为了实现这些目标，我们将使用隔离小动脉(&lt；150Mu m)和 猪冠状动脉微循环内皮细胞的体外培养 实验模型。分离的小动脉将被插管并 加压进行功能研究。培养的细胞将被用来探测 L-精氨酸/一氧化氮代谢改变的机制完好无损的船只 培养细胞研究将相辅相成，以解决 血管功能与内皮细胞L-精氨酸/一氧化氮的关系 在暴露于致动脉粥样硬化剂期间的代谢。来自这些的结果 研究将提供有价值的信息，帮助我们理解 血管功能障碍在血管病变发展中的作用机制 动脉硬化。此外，还阐明了L的抗动脉粥样硬化作用。 精氨酸可能为未来的治疗操作提供基础 高胆固醇血症和/或动脉粥样硬化时的血管功能。