FUNCTIONAL SIGNIFICANCE: CYTOCHROME P450/HEME OXYGENASE

本课题旨在研究血管血红素-血红素加氧酶-一氧化碳系统与细胞色素p450衍生的类二十烷化合物相互作用在调节血管张力和血压中的作用机制及其功能意义。我们将检验四个主要假设。首先，小动脉血管产生的20-HETE受到血管源一氧化碳的抑制调节。其次，血红素氧化酶衍生的一氧化碳对血管张力和反应性的抑制涉及血管20-HETE合成的下调，以及血管平滑肌中Ca2+激活的K+通道的激活。第三，钾摄入量的慢性改变会导致血管血红素加氧酶表达和20-HETE生成的相互变化，进而影响血管反应性，如钾摄入量的增加会促进血管血红素加氧酶表达，降低20-HETE生成，降低血管反应性。第四，实验诱导的高血压大鼠血红素加氧酶过表达的降压作用与一氧化碳生成增加，导致20-HETE合成下调和血管反应性降低有关。在测试这些假设时，将在大鼠中进行以下具体目的的研究。目的1：阐明增加或降低血管血红素-血红素加氧酶-一氧化碳系统活性的干预措施对血管合成20-HETE的影响。目的2：定义血管20-HETE合成在血管对一氧化碳反应的实施和改变血管血红素-血红素加氧酶-一氧化碳系统活性的干预中的意义。目的3：确定一氧化碳20-HETE相互作用对大鼠钾摄入量慢性改变引起的血管反应性变化的贡献。目的4：确定一氧化碳-20- hete相互作用对血红素-血红素加氧酶-一氧化碳系统表达增加引起的血压变化的影响。

This proposal aims at studying the mechanisms and functional significance of the interaction among the vascular heme-heme oxygenase- carbon monoxide system and cytochrome P450-derived eicosanoids in relation to mechanisms regulating vascular tone and blood pressure. Four major hypotheses will be examined. First, the production of 20-HETE by small arterial vessels is subject to inhibitory regulation by carbon monoxide of vascular of origin. Second, the inhibitory of heme oxygenase-derived carbon monoxide on vascular tone and reactivity involves down-regulation of vascular 20-HETE synthesis coupled to activation of Ca2+-activated K+ channels in vascular smooth muscle. Third, chronic alterations in potassium intake brings about reciprocal changes in vascular heme oxygenase expression and 20-HETE production which, in turn, impact on vascular reactivity, e.g., augmentation of potassium intake promotes vascular heme oxygenase expression, decrease 20-HETE production and diminishes vascular reactivity. Fourth, the anti- hypertensive effect accompanying experimentally induced over- expression of heme oxygenase in hypertensive rats is linked to augmentation of carbon monoxide production, leading to down-regulation of 20-HETE synthesis and reduction of vascular reactivity. In testing these hypotheses, the following specific aims will be addressed in rats. AIM 1: To Elucidate the Effect of Interventions That Increase or Decrease the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System on Vascular Synthesis of 20-HETE. AIM 2: To define the Significance of Vascular 20-HETE Synthesis in the Implementation of Vascular Responses to Carbon Monoxide and Interventions That Alter the Activity of the Vascular Heme-Heme Oxygenase-Carbon Monoxide System. AIM 3: To Determine the Contribution of Carbon Monoxide 20-HETE Interactions to the Changes in Vascular Reactivity Caused by Chronic Alterations of Potassium Intake in Rats. AIM 4: Determine the Impact of Carbon Monoxide-20-HETE Interactions on the Changes in Blood Pressure Caused by Interventions That Increased Expression of the Heme-Heme Oxygenase-Carbon Monoxide System.