Microvessel O2 Responses in Salt-Sensitive Hypertension

描述（由申请人提供）：细胞色素P450-4A（CYP 450 -4A）w-羟化酶催化花生四烯酸形成20-羟基-二十碳四烯酸（20-HETE），可作为血管O2传感器，在O2可用性增加和减少期间调节血管张力方面发挥关键作用。我们的研究表明，CYP 450 -20-HETE系统的活性增强是盐敏感型高血压发展过程中通过感知O2可用性和介导外周循环中O2依赖性血管收缩来提高血管阻力的主要候选者。这一提议代表了一系列成功研究的延续，这些研究调查了20-HETE和CYP 450 -4A w-羟化酶在Dahl盐敏感（SS）大鼠中介导对O2可用性变化的反应改变中的作用。本研究中待检验的总体假设是，Dahl SS高血压大鼠中小动脉对PO 2升高的反应增强是由于以下三个因素之一或组合所致：20-HETE的产生增加，血管对20-HETE的血管收缩作用的敏感性增加，和/或细胞色素P450-4A ω-羟化酶的表达改变，对花生四烯酸合成20-HETE进行催化的酶。为了验证这一假设，本研究的具体目的是：1）利用同源和同系大鼠模型，评价细胞色素P450（CYP 450）酶和20-HETE在高盐饮食（HS）改变SS大鼠血管氧反应中的作用; 2）研究HS饮食是否改变了SS大鼠小动脉和阻力动脉中P450-4A β-羟化酶亚型的表达模式，并增加了P450 - 4A β-羟化酶蛋白的表达; 3）、确定与LS饮食的正常血压SS大鼠和缺乏SS CYP 450 -4A等位基因的大鼠品系相比，HS饮食的SS大鼠的小动脉和阻力动脉中20-HETE产生是否升高;和4）为了确定HS饮食是否增加SS大鼠小动脉中的20-HETE敏感性，以及来自缺乏SS CYP 450 - 4A等位基因的大鼠品系的CYP 450基因的渗入是否阻止了任何盐诱导的小动脉20-HETE敏感性增强。这些研究应该提供有价值的洞察力如何血管控制机制改变盐敏感性高血压在人类，特别是在非洲裔美国人的人口，谁表现出一种形式的盐敏感性高血压，这是惊人的相似，发生在达尔SS大鼠。

DESCRIPTION (provided by applicant): Cytochrome P450-4A (CYP450-4A) w-hydroxylase, which catalyzes the formation of 20-hydroxy- eicosatetraenoic acid (20-HETE) from arachidonic acid, may act as a vascular O2 sensor, with a crucial role n regulating vascular tone during both increases and decreases in O2 availability. Our studies indicate that enhanced activity of the CYP450-20-HETE system is a major candidate to elevate vascular resistance during the development of salt sensitive forms of hypertension by sensing O2 availability and mediating O2- dependent vasoconstriction in the peripheral circulation. This proposal represents a continuation of a successful line of studies investigating the role of 20-HETE and CYP450-4A w-hydroxylase in mediating altered responses to changes in O2 availability in the Dahl salt-sensitive (SS) rat. The overall hypothesis to be tested in this study is that the enhanced response of arterioles to elevated PO2 in Dahl SS hypertensive rats is due to one or a combination of three factors: increases in the production of 20-HETE, an increased sensitivity of the vessels to the vasoconstrictor effects of 20-HETE, and/or an altered expression of cytochrome P450-4A w-hydroxylase, the enzyme that catalyzes the synthesis of 20-HETE from arachidonic acid. To test this hypothesis, the proposed study has the following Specific Aims: 1) To utilize consomic and congenic rat models to evaluate the role of cytochrome P450 (CYP450) enzymes and 20-HETE in contributing to altered vascular O2 responses in SS rats on high salt (HS) diet; 2) To determine whether HS diet changes the expression pattern of individual P450-4A w-hydroxylase isoforms and increases CYP- 4504A protein expression in arterioles and resistance arteries of SS rats; 3): To determine whether 20-HETE production is elevated in arterioles and resistance arteries of SS rats on HS diet compared to normotensive SS rats on LS diet and rat strains lacking the SS CYP450-4A alleles; and 4) To determine whether HS diet increases 20-HETE sensitivity in arterioles of SS rats, and whether any salt-induced potentiation of arteriolar 20-HETE sensitivity is prevented by introgression of CYP450 genes from rat strains lacking the SS CYP450- 4A alleles. These studies should provide valuable insight into how vascular control mechanisms are altered during salt-sensitive hypertension in humans, particularly in members of the African-American population, who exhibit a form of salt sensitive hypertension that is strikingly similar to that occurring in the Dahl SS rat.