Role of Xanthine Oxidase in Heme-induced Vascular Dysfunction

黄嘌呤氧化酶在血红素诱导的血管功能障碍中的作用

基本信息

批准号：
10400232
负责人：
Eric Eugene Kelley
金额：
$ 53.44万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10400232
关键词：
Acute Address Allopurinol Binding Biochemical Biological Biological Assay Blood Circulation Blood Vessels Cardiopulmonary Bypass Cardiovascular Surgical Procedures Cell Count Chelating Agents Clinical Clinical effectiveness Data Disease Effectiveness Endothelial Cells Endothelium Enzymes Equilibrium Erythrocytes Generations Globin Glycosaminoglycans Grant Heme Hemin Hemoglobin Hemolysis Hemopexin Hepatic Hepatocyte Human Hydrogen Peroxide Hypertension Hypoxanthines Iatrogenesis Inflammation Inflammatory Inflammatory Response Injury Intervention Iron Iron Chelation Kinetics Knowledge Lead Link Literature Liver Mediating Modeling Mus Operative Surgical Procedures Organ Organ failure Outcome Oxides Pathology Pathway interactions Patients Peptide Hydrolases Permeability Pharmacology Physiological Pilot Projects Plasma Plasma Enhancement Porphyrins Process Production Proteins Publishing Reactive Oxygen Species Regulation Reporting Role Rupture Sepsis Sickle Cell Anemia Source Specific qualifier value Sterility Stress Superoxides Testing Therapeutic Uric Acid Vascular Diseases Vascular System XDH gene Xanthine Oxidase Xanthines base cardiovascular health cardiovascular transplantation chelation clinically significant exhaust febuxostat gain of function heme oxygenase-1 improved mouse model novel overexpression valve replacement vascular injury vaso-occlusive crisis ventricular assist device xanthine oxidase inhibitor

项目摘要

PROJECT SUMMARY/ABSTRACT Vascular injury resulting from hemolysis or ruptured red blood cells is an important clinical issue associated with numerous hemolytic pathologies including sickle cell disease (SCD), sepsis and iatrogenic issues in cardiopulmonary bypass surgery, ventricular assist devices and valve replacement. During hemolysis, red cells release hemoglobin that subsequently discharges heme leading to an oxidative milieu in the intravascular space. Interestingly, substantial elevation in circulating levels of xanthine oxidase (XO) is also reported to be associated with numerous hemolytic diseases. While elevated levels of heme are well characterized in hemolysis pathobiology, the relationship between heme and increased XO activity is unclear. Here, we provide new data connecting a murine model of intravascular heme injury to excessive amplification in circulating XO levels (>20-fold). This is important as decades-long bias in the literature would suggest this level of XO amplification in the circulation to be considered deleterious. Contrary to this long-standing dogma, our new data suggest XO instead assumes a protective role during heme overload. Pilot studies demonstrate inhibition of XO with febuxostat during heme overload decreases survival, accelerates organ damage, and elevates inflammatory responses compared to controls. Consistent with this, plasma from both SCD patients and a murine model of SCD demonstrate elevation in circulating XO. Importantly, biochemical studies have identified a novel function for XO: the “splitting” of heme via H2O2 production and subsequent chelation of heme-derived free iron via uric acid in order to protect the endothelium from overt heme damage. As such, we hypothesize that following hemopexin saturation, hepatic XO is released to the circulation, binds to endothelium, and assumes a vaso- protective role during heme overload and SCD-associated heme crisis due to its ability to degrade heme and subsequently chelate free iron by producing uric acid. We will test this hypothesis using three specific aims: Aim 1: Define if XO mediates protection during intravascular heme overload. Aim 2: Determine if XO facilitates “heme splitting” and subsequent iron chelation via XO-derived uric acid. Aim 3: Investigate whether elevated XO in SCD protects against heme-induced vaso-occlusive crisis. Filling this knowledge gap may uncover new strategies to address the vascular dysfunction allied to intravascular hemolysis, in general, and SCD, in specific.

项目概要/摘要溶血或红细胞破裂引起的血管损伤是一个重要的临床问题与多种溶血病理相关，包括镰状细胞病 (SCD)、败血症和医源性心肺转流手术、心室辅助装置和瓣膜置换术中的问题。红细胞释放血红蛋白，随后释放血红素，导致细胞内形成氧化环境血管内空间中黄嘌呤氧化酶（XO）的循环水平也隐性显着升高。据报道，血红素水平升高与许多溶血性疾病有关。以溶血病理学为特征，血红素与 XO 活性增加之间的关系尚不清楚。在这里，我们提供了将血管内血红素损伤的小鼠模型与过度放大联系起来的新数据循环 XO 水平（>20 倍）这一点很重要，因为文献中长达数十年的偏差表明了这一水平。与这一长期存在的教条相反，我们的新的XO放大被认为是有害的。数据表明，XO 在血红素过载期间发挥保护作用，初步研究表明有抑制作用。 XO 与非布索坦在血红素超负荷期间会降低存活率、加速器官损伤并升高与对照组相比，来自 SCD 患者和小鼠的血浆的炎症反应与此一致。 SCD 模型显示循环 XO 升高。重要的是，生化研究发现了一种新的方法。 XO 的功能：通过产生 H2O2 来“分裂”血红素，并随后螯合血红素衍生的游离铁通过尿酸来保护内皮免受明显的血红素损伤因此，我们采取了以下措施。血红素结合蛋白饱和时，肝脏 XO 被释放到循环中，与内皮结合，并呈现血管- 由于其能够降解血红素并在血红素超载和 SCD 相关血红素危机期间发挥保护作用随后通过产生尿酸来产生游离铁，我们将使用三个具体目标来检验这一假设：目标 1：确定 XO 是否在血管内血红素过载期间介导保护作用。目标 2：确定 XO 是否有促进作用。 “血红素分裂”和随后通过 XO 衍生的尿酸进行铁螯合目标 3：调查是否升高。 XO 在 SCD 中可预防血红素引起的血管闭塞危机填补这一知识空白可能会发现新的发现。一般而言，解决与血管内溶血相关的血管功能障碍以及具体而言与 SCD 相关的血管功能障碍的策略。