OXIDATIVE STRESS, ANTIOXIDANTS AND EDRF ACTION

这一建议是基于这样的假设，即抗氧化剂限制了 冠心病患者的临床表现 保持EDRF动作。 EDRF作用的早期发展 动脉粥样硬化，部分与局部血管过度 氧化应激和氧化低密度脂蛋白的积累 （LDL）。 本申请中提供的最新研究和初步数据 强烈表明氧化应激和 血管壁的抗氧化防御有助于 EDRF作用受损。 总体目标是审查 保护提供的常驻血管细胞内容的抗氧化剂 对于细胞介导的LDL氧化，细胞产生的 活性氧物质如超氧阴离子和过氧化氢， 以及保持EDRF响应氧化损伤的作用。 本提案的主要实验模型将是培养牛 主动脉内皮细胞和平滑肌细胞。 这些问题的相关性 将使用一种新的模型评估LDL氧化在体内的作用， 完整动脉段的LDL氧化。 我们的研究将决定 这些抗氧化剂对细胞产生反应性 氧物种如超氧阴离子和过氧化氢，并开始 调查造成这些影响的机制。 在 特别是，这些影响的关系，对超氧化物和氢 过氧化物的产生，对LDL氧化具有抗氧化剂介导的作用， 将研究EDRF的作用。 我们将研究血管 抗氧化剂含量在保持EDRF行动，以应对各种 氧化损伤包括活性氧和氧化的LDL。 的 本提案所载的工作将提供新的见解， 抗氧化剂为患者提供益处的机制 动脉粥样硬化 特别是，这项工作将有助于确立 血管抗氧化剂的含量在维持体内平衡中起重要作用 功能如局部血管EDRF作用。

This proposal is based on the hypothesis that antioxidants limit the clinical manifestations of coronary artery disease in patients by preserving EDRF action. Abnormalities of EDRF action develop early in atherosclerosis and are related, in part, to excess local vascular oxidative stress and accumulation of oxidized low-density lipoprotein (LDL). Recent studies and preliminary data presented in this application strongly suggest that an imbalance between oxidative stress and antioxidant defenses in the vascular wall contribute to the development of impaired EDRF action. The overall objectives are to examine the protection afforded by the resident vascular cell content of antioxidants with respect to cell-mediated LDL oxidation, the cellular production of reactive oxygen species such as superoxide anion and hydrogen peroxide, and the preservation of EDRF action in response to oxidative insult. The primary experimental model for this proposal will be cultured bovine aortic endothelial and smooth muscle cells. The relevance of these effects for LDL oxidation in vivo will be assessed using a new model of LDL oxidation by intact arterial segments. Our research will determine the effects of these antioxidants on cellular production of reactive oxygen species such as superoxide anion and hydrogen peroxide and begin investigation into the mechanism(s) responsible for these effects. In particular, the relationship of these effects on superoxide and hydrogen peroxide production with antioxidant-mediated effects on LDL oxidation and EDRF action will be studied. We will investigate the role of vascular antioxidant content in preserving EDRF action in response to a variety of oxidative insults including reactive oxygen species and oxidized LDL. The work contained in this proposal will provide new insights into the mechanism(s) by which antioxidants provide benefit for patients with atherosclerosis. In particular, this work will help establish the role of vascular antioxidant content in the preservation of important homeostatic functions such as local vascular EDRF action.