Tetrahydrobiopterin: regulator of endothelial function

四氢生物蝶呤：内皮功能调节剂

基本信息

批准号：
7822183
负责人：
Zvonimir S Katusic
金额：
$ 0.56万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

项目摘要

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. .

内皮功能障碍被定义为在内皮中产生的生物活性一氧化氮（NO）的损失，是血管疾病开始和进展中最重要的事件之一。四氢无菌蛋白（BH4）是一氧化氮合酶的酶活性和生物合成所需的必不可少的辅助因子不。对控制BH4代谢的控制的体内机制知之甚少。期间对于此应用的初步研究，我们将红细胞生成素（EPO）确定为一种新颖而有效的刺激剂心血管系统中的BH4生物合成。 EPO是循环激素负责控制的然而，促红细胞生成的结果表明，EPO具有重要的非肉眼效应包括血管保护。该提议的一般假设是，体内BH4批判性的有助于EPO的血管保护作用。为了检验这一假设，我们提出了以下研究的研究具体目的：1）确定BH4在EPO保护效应中的作用在血管内皮中， 2）确定EPO是否可以防止动脉粥样硬化的发展，3）分析epo-的机制血管损伤后诱导内皮修复。将使用体内遗传和药理方法操纵循环EPO和BH4的水平。建立的内皮功能障碍的鼠模型和将采用血管损伤来确定BH4在EPO血管保护作用的介导中的作用。剖析EPO的直接影响从施加在上面的剪切应力上增加的流变作用内皮通过循环红细胞，新型非肉毒杆菌衍生物的效果将是EPO的影响研究。预计拟议的实验的结果将提供新颖而重要的有关EPO在控制心血管系统中BH4代谢中作用的信息。这信息可能有助于制定预防和治疗内皮功能障碍的新策略。。