Tetrahydrobiopterin: regulator of endothelial function

内皮功能障碍定义为内皮中产生的生物活性一氧化氮（NO）的损失， 是血管疾病发生和发展的重要事件之一。四氢生物蝶呤 (BH4)是一氧化氮合酶的酶活性和 号体内负责控制BH 4代谢的机制知之甚少。期间 对于该应用的初步研究，我们鉴定了促红细胞生成素（EPO）作为一种新的和有效的刺激剂， 心血管系统中的BH 4生物合成。EPO是一种循环激素，负责控制 然而，最近的发现表明EPO具有重要的非红细胞生成作用， 包括血管保护。该建议的一般假设是，在体内，BH 4临界 有助于EPO的血管保护作用。为了验证这一假设，我们提出了以下研究： 具体目的：1）确定BH 4在EPO对血管内皮的保护作用中的介导作用， 2)确定EPO是否可以预防动脉粥样硬化的发展，以及3）分析EPO的机制- 诱导血管损伤后的内皮修复。将使用体内遗传学和药理学方法 来控制循环中EPO和BH 4的水平建立内皮功能障碍的鼠模型， 血管损伤将用于确定BH 4在EPO的血管保护作用的介导中的作用。 为了剖析EPO的直接影响，从其流变学效应，由于剪切应力的增加，施加在 通过循环红细胞对内皮细胞的影响，EPO的新型非红细胞生成衍生物的作用将被 研究了预期所提出的实验的结果将提供新颖且重要的 关于EPO在控制心血管系统中BH 4代谢中的作用的信息。这 这些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. .