MECHANISMS OF VASCULAR DYSFUNCTION IN HOMOCYSTEINEMIA

说明(改编自《调查者摘要》)： 大量的流行病学研究表明 高同型半胱氨酸血症是中风、心肌梗死的危险因素， 和静脉血栓形成。尽管有相对丰富的流行病学数据， 然而，高同型半胱氨酸血症易患血管病变的机制 人们对这些事件仍然知之甚少。已经收到的两个潜在机制 最近的关注是：1)氧化应激增加直接由 同型半胱氨酸氧化或通过抗氧化酶损伤间接氧化 活性和2)内皮细胞一氧化氮介导的生物利用度降低 通过增加一氧化氮的氧化失活或减少 一氧化氮的生成。很少有研究用来测试 假设这些机制在血管的发育中是重要的 体内功能障碍。 在猴子身上使用饮食方法，PI是最早证明 中度高同型半胱氨酸血症与血管受损有关 功能。高同型半胱氨酸血症也与血浆水平升高有关。 不对称二甲基精氨酸(ADMA)，一种内源性一氧化氮抑制物 综合。最近，PI开发了饮食和遗传模型来 造成小鼠高同型半胱氨酸血症和血管功能障碍。 有三个具体目标。AIM 1将使用小鼠模型来确定 血管功能障碍是否由同型半胱氨酸的特异性改变引起 新陈代谢。将对已经产生的两个品系的小鼠进行研究 通过基因打靶技术：敲除胱硫氨酸p-合酶(CBS) 在同型半胱氨酸反式硫化反应中存在选择性缺陷的小鼠，以及 亚甲基四氢叶酸还原酶(MTHFR)基因敲除小鼠，它们有一个 同型半胱氨酸再甲基化的选择性缺陷。目标2，将检验假设 高同型半胱氨酸血症小鼠的血管功能障碍是由 体内的氧化应激。目标3将尝试确定 高同型半胱氨酸血症患者ADMA升高。

DESCRIPTION (Adapted from Investigator's Abstract): A large number of epidemiological studies have suggested that hyperhomocysteinemia is a risk factor for stroke, myocardial infarction, and venous thrombosis. Despite a relative wealth of epidemiological data, however, the mechanisms by which hyperhomocysteinemia predisposes to vascular events remain poorly understood. Two potential mechanisms that have received recent attention are: 1) increased oxidative stress mediated either directly by oxidation of homocysteine or indirectly by impairment of antioxidant enzyme activity and 2) decreased bioavailability of endothelial nitric oxide mediated either by increased oxidative inactivation of nitric oxide or decreased generation of nitric oxide. Very few studies have been performed to test the hypothesis that these mechanisms are important in the development of vascular dysfunction in vivo. Using dietary approaches in monkeys, the PI was among the first to demonstrate that moderate hyperhomocysteinemia is associated with impaired vascular function. Hyperhomocysteinemia was also associated with elevated plasma levels of asymmetric dimethyl arginine (ADMA), an endogenous inhibitor of nitric oxide synthesis. More recently, the PI has developed dietary and genetic models to produce hyperhomocysteinemia and vascular dysfunction in mice. There are three specific aims. Aim 1 will use Murine models to determine whether vascular dysfunction is caused by specific alterations of homocysteine metabolism. Two strains of mice will be studied that have been generated through gene targeting techniques: cystathionine p-synthase (CBS) knockout mice, which have a selective defect in homocysteine trans sulfuration, and methylene tetrahydrofolate reductase (MTHFR) knockout mice, which have a selective defect in homocystine remethylation. Aim 2, will test the hypothesis that vascular dysfunction in hyperhomocysteinemic mice is caused by increased oxidative stress in vivo. Aim 3 will attempt to determine the mechanisms of elevation of ADMA in hyperhomocysteinemia.