Tetrahydrobiopterin: regulator of endothelial function

内皮功能障碍定义为内皮细胞产生的生物活性一氧化氮(NO)的丧失， 是血管疾病发生和发展过程中最重要的事件之一。四氢生物蝶呤 (BH4)是一氧化氮合酶(S)的酶活性和生物合成所必需的辅因子 不是的。在体内，负责控制BH4代谢的机制还知之甚少。在.期间 在这一应用的初步研究中，我们发现促红细胞生成素(EPO)是一种新的和有效的刺激因子 BH4在心血管系统中的生物合成。促红细胞生成素是一种循环激素，负责控制 然而，最近的发现表明，促红细胞生成素具有重要的非红细胞生成作用。 包括血管保护。这一提议的一般假设是，在体内，BH4关键 与促红细胞生成素的血管保护作用有关。为了验证这一假设，我们提出了以下研究 具体目的：1)确定BH4在促红细胞生成素对血管内皮细胞保护作用中的作用； 2)确定EPO是否可以预防动脉粥样硬化的发展；3)分析EPO的作用机制。 诱导血管损伤后的内皮修复。将使用体内遗传和药理学方法 控制血液中EPO和BH4的水平。已建立的小鼠内皮细胞功能障碍和 血管损伤将被用来确定BH4在EPO血管保护作用中的中介作用。 对EPO的直接作用与其因施加在其上的剪应力增加而产生的流变效应进行剖析 通过循环红细胞的内皮，EPO的新的非红细胞生成物的作用将是 学习。预计拟议的实验结果将提供新的和重要的 关于促红细胞生成素在心血管系统中控制BH4代谢的作用的信息。这 信息可能有助于开发预防和治疗内皮功能障碍的新策略。。

Endothelial dysfunction defined as a loss of biologically active nitric oxide (NO) produced in the endothelium, is one of the most important events in initiation and progression of vascular disease. Tetrahydrobiopterin (BH4) is an essential cofactor needed for enzymatic activity of nitric oxide synthase(s) and biosynthesis of NO. In vivo mechanisms responsible for the control of BH4 metabolism are poorly understood. During preliminary studies for this application we identified erythropoietin (EPO) as a novel and potent stimulator of BH4 biosynthesis in the cardiovascular system. EPO is circulating hormone responsible for control of erythropoiesis, however, more recent findings suggest that EPO has important non-erythropoietic effects including vascular protection. The general hypothesis of this proposal is that in vivo, BH4 critically contributes to the vascular protective effect of EPO. To test this hypothesis we propose studies with following specific aims: 1) determine the role of BH4 in mediation of protective effectsof EPO in vascular endothelium, 2) determine if EPO may prevent development of atherosclerosis, and 3) analyze the mechanisms of EPO- induced endothelial repair after vascular injury. In vivo genetic and pharmacological approaches will be used to manipulate levels of circulating EPO and BH4. Established murine models of endothelial dysfunction and vascular injury will be employed to determine role of BH4 in mediation of vascular protective effects of EPO. To dissect direct effects of EPO from its rheological effects due to increase in shear stress imposed on endothelium by circulating erythrocytes, effects of novel non-erythropoietic derivatives of EPO will be studied. It is anticipated that the results of the proposed experiments will provide novel and important information concerning the role of EPO in control of BH4 metabolism in the cardiovascular system. This information may help to develop new strategies in prevention and treatment of endothelial dysfunction. .