HEME OXYGENASE REGULATION OF EICOSANOID BIOSYNTHESIS

描述（来自申请的逐字）：血红素加氧酶（HO）催化 血红素转化为胆绿素、游离铁和一氧化碳（GO）。血红素是 血红素蛋白的合成/活性所需的，可以影响血管和 肾功能，如类花生酸生物合成酶、细胞色素P450 (GYP)单加氧酶、血栓素和前列环素脱氢酶，以及 环加氧酶（考克斯）。HO控制细胞血红素浓度， 负责产生血管抑制剂CO，其本身可以 与血红素蛋白的血红素部分结合，引起酶活化或 抑制作用诱导HO抑制肾脏花生四烯酸（AA）代谢 通过GYP和考克斯/血栓烷合酶活性转化为升压代谢物， 与尿钠排泄和血压降低相关，并通过以下方法预防 HO抑制剂，表明HO衍生的血红素消耗和/或CO生成 这些影响的基础。一氧化碳或血红素诱导的一氧化碳舒张血管作用 并降低SHR的血压。两种HO异构体已被 被鉴定为HO活性的主要来源，诱导型HO-1和诱导型HO-2被鉴定为HO活性的主要来源。 组成型表达的HO-2。新发现的HO-3同工型共有90 与HO-2的同源性百分比，并且缺乏显著的催化活性。的 肾脏内各亚型对HO活性的分布和贡献 不明我们证实了肾组织中HO-2的水平相对较高， 微血管和髓质粗升支，而近端小管 表现出高水平的HO-i。我们提出HO亚型是不同的， 定位于肾脏结构，并有助于调节GYP和考克斯 活动，从而调节类二十烷酸的形成， 血管舒缩和调节离子转运。拟议的研究将：1）本地化 HO同工型在大鼠肾脏内的表达和活性; 2）检测HO同工型在大鼠肾脏内的表达和活性。 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;和3）研究这些操作在 确定HO同工型与肾考克斯的功能关系， GYP依赖的类花生酸生物合成。研究HO在肾脏结构中的作用 正常血压和高血压大鼠以及肾HO已被 改变将建立HO同种型表达的局部变化， 与考克斯的表达及CYP-AA代谢有关。这些研究考察了 HO活性对这些血红素蛋白的影响将揭示可能的 HO的低表达/过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.