The impact of xanthine oxidase (XO) on hemolytic diseases
Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules or indirectly by upregulating enzymatic sources of reactive species. A key enzymatic source of these reactive species is the purine...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-02-01
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| Series: | Redox Biology |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231718309868 |
| _version_ | 1811215004754509824 |
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| author | Heidi M. Schmidt Eric E. Kelley Adam C. Straub |
| author_facet | Heidi M. Schmidt Eric E. Kelley Adam C. Straub |
| author_sort | Heidi M. Schmidt |
| collection | DOAJ |
| description | Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules or indirectly by upregulating enzymatic sources of reactive species. A key enzymatic source of these reactive species is the purine catabolizing enzyme, xanthine oxidase (XO) as the oxidation of hypoxanthine to xanthine and subsequent oxidation of xanthine to uric acid generates superoxide (O2•-) and hydrogen peroxide (H2O2). While XO has been studied for over 120 years, much remains unknown regarding specific mechanistic roles for this enzyme in pathologic processes. This gap in knowledge stems from several interrelated issues including: 1) lethality of global XO deletion and the absence of tissue-specific XO knockout models have coalesced to relegate proof-of-principle experimentation to pharmacology; 2) XO is mobile and thus when upregulated locally can be secreted into the circulation and impact distal vascular beds by high-affinity association to the glycocalyx on the endothelium; and 3) endothelial-bound XO is significantly resistant (> 50%) to inhibition by allopurinol, the principle compound used for XO inhibition in the clinic as well as the laboratory. While it is known that circulating XO is elevated in hemolytic diseases including sickle cell, malaria and sepsis, little is understood regarding its role in these pathologies. As such, the aim of this review is to define our current understanding regarding the effect of hemolysis (free heme) on circulating XO levels as well as the subsequent impact of XO-derived oxidants in hemolytic disease processes. Keywords: Hemolysis, Heme toxicity, Xanthine oxidase, Reactive oxygen species, Therapeutics |
| first_indexed | 2024-04-12T06:14:59Z |
| format | Article |
| id | doaj.art-812e4bbad40b41a3bf4fe30007144c28 |
| institution | Directory Open Access Journal |
| issn | 2213-2317 |
| language | English |
| last_indexed | 2024-04-12T06:14:59Z |
| publishDate | 2019-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj.art-812e4bbad40b41a3bf4fe30007144c282022-12-22T03:44:32ZengElsevierRedox Biology2213-23172019-02-0121The impact of xanthine oxidase (XO) on hemolytic diseasesHeidi M. Schmidt0Eric E. Kelley1Adam C. Straub2Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United StatesDepartment of Physiology and Pharmacology, West Virginia University, School of Medicine, Morgantown, WV, United States; Correspondence to: West Virginia University, School of Medicine, Department of Physiology and Pharmacology, 3075 North Health Sciences Center, 1 Medical Center Drive, Morgantown, WV 064, United States.Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, United States; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, United States; Corresponding author at: University of Pittsburgh School of Medicine, Department of Pharmacology and Chemical Biology, The Heart, Lung, Blood and Vascular Medicine Institute, E1254 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15216, United States.Hemolytic diseases are associated with elevated levels of circulating free heme that can mediate endothelial dysfunction directly via redox reactions with biomolecules or indirectly by upregulating enzymatic sources of reactive species. A key enzymatic source of these reactive species is the purine catabolizing enzyme, xanthine oxidase (XO) as the oxidation of hypoxanthine to xanthine and subsequent oxidation of xanthine to uric acid generates superoxide (O2•-) and hydrogen peroxide (H2O2). While XO has been studied for over 120 years, much remains unknown regarding specific mechanistic roles for this enzyme in pathologic processes. This gap in knowledge stems from several interrelated issues including: 1) lethality of global XO deletion and the absence of tissue-specific XO knockout models have coalesced to relegate proof-of-principle experimentation to pharmacology; 2) XO is mobile and thus when upregulated locally can be secreted into the circulation and impact distal vascular beds by high-affinity association to the glycocalyx on the endothelium; and 3) endothelial-bound XO is significantly resistant (> 50%) to inhibition by allopurinol, the principle compound used for XO inhibition in the clinic as well as the laboratory. While it is known that circulating XO is elevated in hemolytic diseases including sickle cell, malaria and sepsis, little is understood regarding its role in these pathologies. As such, the aim of this review is to define our current understanding regarding the effect of hemolysis (free heme) on circulating XO levels as well as the subsequent impact of XO-derived oxidants in hemolytic disease processes. Keywords: Hemolysis, Heme toxicity, Xanthine oxidase, Reactive oxygen species, Therapeuticshttp://www.sciencedirect.com/science/article/pii/S2213231718309868 |
| spellingShingle | Heidi M. Schmidt Eric E. Kelley Adam C. Straub The impact of xanthine oxidase (XO) on hemolytic diseases Redox Biology |
| title | The impact of xanthine oxidase (XO) on hemolytic diseases |
| title_full | The impact of xanthine oxidase (XO) on hemolytic diseases |
| title_fullStr | The impact of xanthine oxidase (XO) on hemolytic diseases |
| title_full_unstemmed | The impact of xanthine oxidase (XO) on hemolytic diseases |
| title_short | The impact of xanthine oxidase (XO) on hemolytic diseases |
| title_sort | impact of xanthine oxidase xo on hemolytic diseases |
| url | http://www.sciencedirect.com/science/article/pii/S2213231718309868 |
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