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：
10582635
负责人：
Eric Eugene Kelley
金额：
$ 53.62万
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/10582635
关键词：
Acceleration Acute Address Allopurinol Ally Binding Biochemical Biological Biological Assay Blood Vessels Cardiopulmonary Bypass Cardiovascular Surgical Procedures Cell Count Circulation Clinical 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 Iron Iron Chelating Agents Iron Chelation Kinetics Knowledge Link Literature Liver Mediating Modeling Mus Operative Surgical Procedures Organ Organ failure Outcome Pathology Pathway interactions Patients Peptide Hydrolases Permeability Pharmacology Physiological Pilot Projects Plasma Plasma Enhancement Porphyrins Probability 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 cardiovascular health cardiovascular transplantation chelation clinically significant comparison control coping 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.

项目摘要/摘要溶血或红细胞破裂引起的血管损伤是重要的临床问题与包括镰状细胞疾病（SCD），败血症和医源性的许多溶血性病理有关心肺旁路手术，心室辅助设备和瓣膜更换的问题。在溶血期间，红细胞释放血红蛋白，随后排出血红素，导致氧化环境血管内空间。有趣的是，循环水平的黄嘌呤氧化物（XO）的高度升高也是据报道与许多溶血疾病有关。虽然血红素水平升高在溶血病理学中的特征，血红素与XO活性增加之间的关系尚不清楚。在这里，我们提供了新的数据，该数据将血管内血红素损伤的鼠模型与过量扩增循环XO水平（> 20倍）。这很重要，因为文献中长达数十年的偏见表明这一水平在循环中被认为已删除的XO扩增。与这个长期存在的教条相反，我们的新教条数据表明，XO相反，在血红素过载过程中承担了受保护的作用。试点研究表明抑制作用血红素过载期间有XO的XO，XO的生存下降，加速器官损害并提升与对照组相比，炎症反应。与此相一致，来自SCD患者和鼠的血浆 SCD模型表明循环XO的升高。重要的是，生化研究已经确定了一种新颖 XO的功能：血红素通过H2O2的产生和随后的血红素衍生的自由铁的“分裂” 通过尿酸保护内皮免受明显的血红素损伤。因此，我们假设以下肝脏XO的血红素饱和度释放到循环中，与内皮结合，并假定具有血管血红素过载和SCD相关的血红素危机期间的保护作用，因为它能够降解血红素和随后通过产生尿酸作弊。我们将使用三个特定目标检验这一假设： AIM 1：定义XO是否在血管血红素过载期间介导保护。 AIM 2：确定XO是否最爱通过XO衍生的尿酸进行“血红素分裂”和随后的铁螯合。目标3：调查是否提升 SCD中的XO防止血红素引起的血管熟悉危机。填补此知识差距可能会发现新的特别是针对与血管内溶血相关的血管功能障碍的策略。