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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.

项目总结/文摘