HEME OXYGENASE REGULATION OF EICOSANOID BIOSYNTHESIS

描述(逐字摘自申请)：血红素加氧酶(HO)催化 将血红素转化为胆绿素、游离铁和一氧化碳(GO)。亚铁血红素是 血红素蛋白的合成/活性所必需的，它可以影响血管和 肾功能，如二十烷类生物合成酶，细胞色素P450 (GYP)单加氧酶、血栓素和前列环素合成酶和 环氧合酶(COX)。HO控制细胞内的血红素浓度，是唯一的 负责血管降压剂CO的产生，它本身可以 结合到血红素蛋白的血红素部分，导致酶激活或 抑制力。HO诱导抑制肾脏花生四烯酸(AA)代谢 通过Gyp和COX/血栓素合酶活性使代谢产物升压，是 与钠尿和血压降低有关，并通过以下方式预防 HO抑制剂，提示HO来源的血红素耗尽和/或CO的产生 这是这些影响的基础。一氧化碳或高铁血红素产生的一氧化碳在体外引起血管扩张 在体内，并降低自发性高血压大鼠的血压。已经有两种HO亚型 被确定为HO活性的主要来源，可诱导的HO-I和 结构性表达的HO-2。新发现的HO-3亚型共享90 与HO-2的同源性较高，缺乏明显的催化活性。这个 各亚型在肾脏内的分布及其对HO活性的贡献 是未知的。我们发现肾脏中的HO-2水平相对较高 微血管和髓质粗升肢，近端小管 显示出高水平的HO-I。我们认为HO亚型是不同的 定位于肾脏结构，参与Gyp和COX的调节 活性，从而调节二十烷类化合物的形成，影响 血管运动和调节离子运输。拟议的研究将：1)本地化 HO亚型在大鼠肾脏中的表达和活性；2)检测 HO诱导剂和选择性抑制剂对HO亚型表达的影响 在肾脏中的分布；以及3)研究这些动作在 确定HO亚型与肾脏COX和HO的功能关系 依赖于Gyp的二十烷类化合物的生物合成。HO在大鼠肾脏结构中的研究 正常血压和高血压大鼠以及肾脏HO已 改变将建立HO异构体表达的局部变化，因为它们 与COX的表达和CYP-AA的代谢有关。研究考察了 HO活性对这些血红素蛋白的影响将有助于揭示可能的 HO低表达/高表达影响血管张力的机制 离子转运和血压。

DESCRIPTION (Verbatim from the application): Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (GO). Heme is required for synthesis/activity of heme proteins that can affect vascular and renal function such as the eicosanoid biosynthetic enzymes, cytochrome P450 (GYP) monooxygenases, thromboxane and prostacyclin synthases and cyclooxygenases (COX). HO controls cellular heme concentrations and is solely responsible for the generation of the vasodepressor CO which, by itself, can bind to the heme moiety of heme proteins causing either enzyme activation or inhibition. Induction of HO suppresses renal arachidonic acid (AA) metabolism to pressor metabolites via GYP and COX/thromboxane synthase activities, is associated with natriuresis and blood pressure reduction, and is prevented by HO inhibitors, suggesting that HO-derived heme depletion and/or CO generation underlie these effects. CO or HOheme-generated CO elicits vasodilation in vitro and in vivo and reduces blood pressure in the SHR. Two HO isoforms have been identified as the primary source of HO activity, the inducible HO-i and the constitutively-expressed HO-2. The newly discovered HO-3 isoform share 90 percent homology with HO-2 and lack significant catalytic activity. The distribution and contribution of each isoform to HO activity within the kidney is unknown. We demonstrated relatively high levels of HO-2 in the renal microvessels and the medullary thick ascending limb, whereas proximal tubules exhibit high levels of HO-i. We propose that HO isoforms are differentially localized in kidney structures and contribute to the regulation of GYP and COX activities, thereby regulating the formation of eicosanoids that affect vasomotion and modulate ion transport. The proposed studies will: 1) localize HO isoforms expression and activity within the rat kidney; 2) examine the effect of HO inducers and selective inhibitors on HO isoforms expression and distribution in the kidney; and 3) study the effect of these maneuvers in determining the functional relationship of HO isoforms to renal COX and GYP-dependent eicosanoid biosynthesis. Studying HO in renal structures of normotensive and hypertensive rats and in rats in which renal HO has been altered will establish local changes in the expression of HO isoforms as they relate to the expression of COX and CYP-AA metabolism. Studies that examine the influence of HO activity on these heme proteins will shed light on possible mechanisms by which underexpression/overexpression of HO affects vascular tone, ion transport and blood pressure.