Modulation of Enothelial Vasomotor and Antithrombotic Functions by Antioxidants,

超氧化物和其他活性氧在多种血管疾病中起着关键作用。这 项目延续了项目的最初主题，涉及超氧化物对内皮功能的影响， 动脉粥样硬化和消退后，与血栓形成和抗血栓形成机制的新重点。 目的1是研究一种重要的抗氧化酶--细胞外超氧化物歧化酶的作用 （ECSOD）和该酶的常见人类基因变体。调查人员报告说， 肝素结合区（HBD）是ECSOD正常功能所必需的。一个共同的基因 ECSOD的HBD变异体R213 G可能是缺血性心脏病的一个非常重要的危险因素 疾病研究人员已经制备了表达ECSOD R213 G的重组腺病毒， 研究基因变异对血管的影响。有人提出研究来检验这一假设， ECSOD，而不是ECSOD R213 G，减轻炎症并保护细菌感染后的内皮功能。 内毒素 目的2是研究动脉粥样硬化和ECSOD对内皮抗血栓的影响 功能和对血栓形成的易感性。有人提出研究来检验这一假设， 动脉粥样硬化小鼠中的加速血栓形成是由氧化应激和生物利用度降低引起的 内皮源性一氧化氮，抗凝蛋白C的活化降低。的影响 动脉粥样硬化对内皮抗血栓功能的影响也将在一种新的基因敲入菌株中进行研究。 表达人血栓调节蛋白并具有降低的激活抗凝蛋白能力的小鼠 C. 目的3是研究动脉粥样硬化消退对内皮血管的影响， 小鼠抗血栓形成功能。在“逆转”小鼠中，高胆固醇血症可以通过遗传逆转， 开关. Cre诱导后，微粒体甘油三酯转移蛋白基因几乎被消除， LDLr-/- apoB 100/100小鼠的血浆胆固醇降低至正常水平。建议进行研究 为了检验Reversa小鼠中动脉粥样硬化消退改善内皮血管扩张的假设， 在主动脉和冠状动脉中的功能，减少血管和主动脉瓣中的过氧化物， 逆转血栓形成的易感性。项目3的长期目标是澄清 超氧化物和抗氧化酶调节内皮血管活性的基本机制 和抗血栓功能。

Superoxide and other reactive oxygen species play a pivotal role in a variety of vascular diseases. This project continues the initial theme of the project, related to effects of superoxide on endothelial function in atherosclerosis and after regression, with a new emphasis on thrombotic and antithrombotic mechanisms. The goal of Aim 1 is to study effects of an important antioxidant enzyme, extracellular superoxide dismutase (ECSOD) and a common human gene variant of that enzyme. The investigators reported that the heparin-binding domain (HBD) of ECSOD is essential for normal functon of ECSOD. A common gene variant in the HBD of ECSOD, R213G, may be an extremely important risk factor for ischemic heart disease. The investigators have made a recombinant adenovirus that expresses ECSOD R213G and propose to examine vascular effects of the gene variant. Studies are proposed to test the hypothesis that ECSOD, but not ECSOD R213G, attenuates inflammation and protects endothelial function after bacterial endotoxin. The goal of Aim 2 is to examine effects of atherosclerosis and ECSOD on endothelial antithrombotic func-tion and susceptibility to thrombosis in mice. Studies are proposed to test the hypothesis that accelerated thrombosis in atherosclerotic mice is caused by oxidative stress and decreased bioavailability of endothe-lium-derived nitric oxide, with decreased activation of anticoagulant protein C. Effects of atherosclerosis on endothelial antithrombotic function also will be examined in a novel strain of knock-in mice that express human thrombomodulin and have diminished capacity to activate anticoagulant protein C. The goal of Aim 3 is to examine effects of regression of atherosclerosis on endothelial vasomotor and anti-thrombotic function in mice. In "Reversa" mice, hypercholesterolemia can be reversed with a genetic switch. After Cre induction, the gene for microsomal triglyceride transfer protein is virtually eliminated, so that plasma cholesterol in LDLr-/- apoB 100/100 mice is reduced to normal levels. Studies are proposed to test the hypothesis that regression of atherosclerosis in Reversa mice improves endothelial vasomotor function in aorta and coronary arteries, reduces superoxide in blood vessels and aortic valve, and reverses the enhanced susceptibility to thrombosis. The long-term goal of Project 3 is to clarify fundamental mechanisms by which superoxide and antioxidant enzymes modulate endothelial vasomotor and antithrombotic function.