MECHANISMS OF VASCULAR DYSFUNCTION IN HOMOCYSTEINEMIA

描述（改编自研究者摘要）： 大量的流行病学研究表明， 高同型半胱氨酸血症是中风，心肌梗塞， 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倾向于血管性的机制， 人们对事件的了解仍然很少。两个潜在的机制已经收到 最近的关注是：1）增加的氧化应激直接由 同型半胱氨酸氧化或间接通过抗氧化酶损伤 活性和2）降低内皮一氧化氮介导的生物利用度 通过增加一氧化氮的氧化失活或减少 一氧化氮的生成。很少有研究已经进行测试， 假设这些机制在血管的发展中很重要， 体内功能障碍。 通过在猴子身上使用饮食方法，PI是第一批证明 中度高同型半胱氨酸血症与受损的血管 功能高同型半胱氨酸血症也与血浆水平升高有关 内源性一氧化氮抑制剂不对称二甲基精氨酸（ADMA） 合成.最近，PI开发了饮食和遗传模型， 在小鼠中产生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.将研究两种小鼠， 通过基因靶向技术：胱硫醚β-合酶（CBS）敲除 小鼠，其在高半胱氨酸转硫中具有选择性缺陷，和 亚甲基四氢叶酸还原酶（MTHFR）敲除小鼠，其具有 高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 体内氧化应激。目标3将试图确定 高同型半胱氨酸血症中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.