Vasoregulatory Function of CYP2E1-Derived Eicosanoids

本研究旨在探讨细胞色素P450 2 E1（CYP 2 E1）衍生的细胞色素P450 2 E1（CYP 2 E1） 类花生酸调节大鼠和小鼠血管收缩反应性和血压。 该提案的重点是CYP 2 E1依赖性血管生成19（R）-和18（R）- 羟基二十碳四烯酸（HETE）、此类类二十烷酸的血管调节作用及其 与20-HETE的相互作用，以及19（R）-和18（R）-HETE有助于抗高血压的观点 通过干扰20-HETE诱导的血管平滑肌对收缩肌的敏感性发挥作用 刺激。将致力于实现以下目标。目的1：检验高血压 血管CYP 2 E1和19（R）-和18（R）-HETE合成的抑制性减少，伴随 放大20-HETE诱导的对收缩刺激的敏感性， 血管反应性研究将在SHR中进行，在大鼠中通过用 脱氧皮质酮或血管紧张素II，以及血压正常的对照。我们试图确定其 血压水平、血管CYP 2 E1表达和对 收缩刺激受20-HETE和CYP 2 E1衍生类花生酸的影响。目标2：测试 性别、膳食钾和膳食钠影响血管CYP 2 E1表达假说 和19（R）-和18（R）-HETE的合成，伴随着收缩反应性的相应改变 由于20-HETE依赖性血管生成机制的有效性发生变化， 对收缩肌刺激的敏感性。我们将探讨血管CYP 4A和CYP 2 E1之间的关系 表达，20-，19（R）-和18（R）-HETE的合成，以及对缩窄肌刺激的反应性， 性别与膳食钾、钠的作用。目的3：检验上调 血管CYP 2 E1表达和19（R）-和18（R）-HETE合成的抑制 高血压CYP 2 E1基因转移对血压、血管CYP 2 E1和 CYP衍生的类二十烷酸的合成，以及血管系统对收缩刺激的反应性将是 在SHR中探索，大鼠通过血管紧张素II输注或注射腺病毒 表达CYP 4A 2的构建体。目的4：验证血管CYP 2 E1降低 活性和/或表达促进血压升高。我们试图确定血液 大鼠的血压和血压对血管紧张素II输注的反应性增强 经历CYP 2 E1抑制，以及在CYP 2 E1缺失小鼠中。

This is a proposal to investigate the role played by cytochrome P450 2E1 (CYP2E1 )-deriyed eicosanoids in the regulation of vasoconstrictor responsiveness and blood pressure in rats and mice. The proposal focuses on CYP2E1-dependent vascular production of 19(R)- and 18(R)- hydroxyeicosatetraenoic acids (HETE), the vasoregulatory action of such eicosanoids and their interaction with 20-HETE, and the notion that 19(R)- and 18(R)-HETE subserve antihypertensive functions by interfering with 20-HETE-induced sensitization of vascular smooth muscle to constrictor stimuli. The following aims will be addressed. AIM 1: To test the hypothesis that high blood pressure elicits reduction of vascular CYP2E1 and synthesis of 19(R)- and 18(R)-HETE, with attendant amplification of 20-HETE-induced sensitization to constrictor stimuli bringing about augmentation of vascular reactivity. Studies will be conducted in SHR, in rats made hypertensive by treatment with deoxycorticosterone or angiotensin II, and in normotensive controls. We seek to determine relationships between the level of blood pressure, vascular CYP2E1 expression and reactivity to constrictor stimuli as affected by 20-HETE and CYP2E1-derived eicosanoids. AIM 2: To test the hypothesis that gender, dietary potassium and dietary sodium influence vascular CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE, with consequential alterations in constrictor responsiveness resulting from changes in the effectiveness of the 20-HETE-dependent mechanism of vascular sensitization to constrictor stimuli. We will explore relationships between vascular CYP4A and CYP2E1 expression, synthesis of 20-, 19(R)- and 18(R)-HETE, and responsiveness to constrictor stimuli as a function of gender and dietary potassium and sodium. AIM 3: To test the hypothesis that upregulation of vascular CYP2E1 expression and synthesis of 19(R)- and 18(R)-HETE attenuates the development of hypertension. The effects of CYP2E1 gene transfer on blood pressure, vascular CYP2E1 and synthesis of CYP-derived eicosanoids, and reactivity of the vasculature to constrictor stimuli will be explored in SHR, and rats made hypertensive by angiotensin II infusion or injection of an adenoviral construct expressing CYP4A2. AIM 4: To test the hypothesis that reduction of vascular CYP2E1 activity and/or expression promotes elevation of blood pressure. We seek to determine whether blood pressure and blood pressure responsiveness to angiotensin II infusion are enhanced in rats undergoing inhibition of CYP2E1, and in CYP2E1-null mice.