Xanthine Oxidase Drives Hemolysis and Vascular Malfunction in Sickle Cell Disease
| Autor: | Adam C. Straub, Jianhai Du, Samit Ghosh, Heidi M Schmidt, Brenda McMahon, Jeffrey D. Lebensburger, Solomon F. Ofori-Acquah, Scott A. Hahn, Yekai Wang, Joo-Yeun Oh, Shuai Yuan, Katherine C. Wood, Jeffrey J. Baust, Sara E. Lewis, Dario A. Vitturi, Eric E. Kelley, Timothy N. Bachman, Rakesh P. Patel, Xena M. Williams |
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| Rok vydání: | 2021 |
| Předmět: |
Male
0301 basic medicine Xanthine Oxidase Erythrocytes Endothelium Cell Anemia Sickle Cell Disease Pulmonary Artery 030204 cardiovascular system & hematology Hemolysis Article 03 medical and health sciences chemistry.chemical_compound Febuxostat 0302 clinical medicine medicine Animals Ventricular Function Anemia sickle-cell Enzyme Inhibitors Xanthine oxidase Mice Knockout business.industry Hemodynamics medicine.disease Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Liver chemistry Immunology Bone marrow Cardiology and Cardiovascular Medicine business medicine.drug |
| Zdroj: | Arterioscler Thromb Vasc Biol |
| ISSN: | 1524-4636 1079-5642 |
| Popis: | Objective: Chronic hemolysis is a hallmark of sickle cell disease (SCD) and a driver of vasculopathy; however, the mechanisms contributing to hemolysis remain incompletely understood. Although XO (xanthine oxidase) activity has been shown to be elevated in SCD, its role remains unknown. XO binds endothelium and generates oxidants as a byproduct of hypoxanthine and xanthine catabolism. We hypothesized that XO inhibition decreases oxidant production leading to less hemolysis. Approach and Results: Wild-type mice were bone marrow transplanted with control (AA) or sickle (SS) Townes bone marrow. After 12 weeks, mice were treated with 10 mg/kg per day of febuxostat (Uloric), Food and Drug Administration–approved XO inhibitor, for 10 weeks. Hematologic analysis demonstrated increased hematocrit, cellular hemoglobin, and red blood cells, with no change in reticulocyte percentage. Significant decreases in cell-free hemoglobin and increases in haptoglobin suggest XO inhibition decreased hemolysis. Myographic studies demonstrated improved pulmonary vascular dilation and blunted constriction, indicating improved pulmonary vasoreactivity, whereas pulmonary pressure and cardiac function were unaffected. The role of hepatic XO in SCD was evaluated by bone marrow transplanting hepatocyte-specific XO knockout mice with SS Townes bone marrow. However, hepatocyte-specific XO knockout, which results in >50% diminution in circulating XO, did not affect hemolysis levels or vascular function, suggesting hepatocyte-derived elevation of circulating XO is not the driver of hemolysis in SCD. Conclusions: Ten weeks of febuxostat treatment significantly decreased hemolysis and improved pulmonary vasoreactivity in a mouse model of SCD. Although hepatic XO accounts for >50% of circulating XO, it is not the source of XO driving hemolysis in SCD. |
| Databáze: | OpenAIRE |
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