FUNCTIONAL SIGNIFICANCE: CYTOCHROME P450/HEME OXYGENASE

本研究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衍生的类花生酸之间相互作用的机制及其在调节血管张力和血压方面的功能意义。将检验四个主要假设。首先，小动脉血管产生的20-HETE受到血管来源一氧化碳的抑制性调节。第二，血红素加氧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，其与血管平滑肌中Ca 2+激活的K+通道的激活偶联。第三，钾摄入的慢性改变引起血管血红素加氧酶表达和20-HETE产生的相互变化，这反过来影响血管反应性，例如，增加钾的摄入促进血管血红素氧合酶的表达，减少20-HETE的产生并降低血管反应性。第四，在高血压大鼠中伴随实验诱导的血红素加氧酶过度表达的抗高血压作用与一氧化碳产生的增加有关，导致20-HETE合成的下调和血管反应性的降低。在测试这些假设时，将在大鼠中解决以下具体目标。目标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。目标2：确定血管20-HETE合成在实施血管对一氧化碳的反应和改变血管血红素-血红素加氧酶-一氧化碳系统活性的干预中的意义。目标3：确定一氧化碳20-HETE相互作用对大鼠钾摄入量慢性变化引起的血管反应性变化的贡献。目标4：确定一氧化碳-20-HETE相互作用对增加血红素-血红素加氧酶-一氧化碳系统表达的干预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.