Mechanisms of Vascular Dysfunction in Homocysteinemia

描述（由申请人提供）：高同型半胱氨酸血症，或血浆总同型半胱氨酸升高，是心血管疾病和中风的新危险因素。大量回顾性和前瞻性研究表明，高同型半胱氨酸血症是一个独立的危险因素，其危险程度与高胆固醇血症或高血压等传统危险因素相似。降低同型半胱氨酸治疗的潜在心血管益处目前正在几个前瞻性临床试验中进行评估。然而，尽管高同型半胱氨酸血症与临床心血管疾病有明显的关联，但其血管病理机制仍不完全清楚。我们的小组是第一个证明中度高同型半胱氨酸血症在体内产生血管功能受损的小组。为了更好地研究高同型半胱氨酸血症中血管功能障碍的机制，我们开发了遗传和饮食方法来产生小鼠高同型半胱氨酸血症。我们的数据和其他数据提供了强有力的证据，证明高同型半胱氨酸血症期间内皮功能障碍与内皮源性一氧化氮（NO）的生物利用度受损有关。提出的机制包括不对称二甲基精氨酸（ADMA）抑制内皮一氧化氮合酶导致NO氧化失活和NO生成减少。该项目的目标是确定ADMA在降低NO生物利用度中的作用，并确定高同型半胱氨酸血症中介导血管功能障碍的活性氧（ROS）的来源。我们的实验设计的一个关键特征是使用转基因小鼠来检测ADMA，一氧化氮合酶的诱导异构体和血管NAD(P)H氧化酶在高同型半胱氨酸血症期间损害内皮功能的作用。该项目有可能为预防和治疗与高同型半胱氨酸血症相关的血管疾病提供新的治疗方法。

DESCRIPTION (provided by applicant): Hyperhomocysteinemia, or elevation of plasma total homocysteine, is an emerging risk factor for cardiovascular disease and stroke. Numerous retrospective and prospective studies have suggested that hyperhomocysteinemia is an independent risk factor, and that the magnitude of risk is similar to that for conventional risk factors such as hypercholesterolemia or hypertension. The potential cardiovascular benefits of homocysteine-lowering therapy are currently being evaluated in several prospective clinical trials. Despite its clear association with clinical cardiovascular disease, however, the mechanisms responsible for the vascular pathology of hyperhomocysteinemia are still incompletely understood. Our group was among the first to demonstrate that moderate hyperhomocysteinemia produces impaired vascular function in vivo. To better examine the mechanisms of vascular dysfunction in hyperhomocysteinemia, we have developed genetic and dietary approaches to produce hyperhomocysteinemia in mice. Our data, and data from others, have provided strong evidence that endothelial dysfunction during hyperhomocysteinemia is related to impaired bioavailability of endothelium-derived nitric oxide (NO). Proposed mechanisms include oxidative inactivation of NO and decreased production of NO due to inhibition of endothelial nitric oxide synthase by asymmetric dimethylarginine (ADMA). The goals of this project are to define the role of ADMA in decreasing NO bioavailability and to determine the sources of reactive oxygen species (ROS) that mediate vascular dysfunction in hyperhomocysteinemia. A key feature of our experimental design is the use of genetically-altered mice to examine the contributions of ADMA, the inducible isoform of nitric oxide synthase, and vascular NAD(P)H oxidases in impairing endothelial function during hyperhomocysteinemia. This project has the potential to suggest novel therapeutic approaches to the prevention and treatment of vascular disease associated with hyperhomocysteinemia.