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Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide.
Shi, Hui; Gandhi, Alex A; Smith, Stephanie A; Wang, Qiuyu; Chiang, Diane; Yalavarthi, Srilakshmi; Ali, Ramadan A; Liu, Chao; Sule, Gautam; Tsou, Pei-Suen; Zuo, Yu; Kanthi, Yogendra; Farkash, Evan A; Lin, Jiandie D; Morrissey, James H; Knight, Jason S.
  • Shi H; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Gandhi AA; Division of Rheumatology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • Smith SA; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Wang Q; Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan, USA.
  • Chiang D; Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
  • Yalavarthi S; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Ali RA; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Liu C; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Sule G; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Tsou PS; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Zuo Y; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Kanthi Y; Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.
  • Farkash EA; Division of Intramural Research National Heart, Lung and Blood Institute Bethesda, Maryland, USA.
  • Lin JD; Division of Cardiovascular Medicine, Department of Internal Medicine and.
  • Morrissey JH; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
  • Knight JS; Life Sciences Institute and Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, Michigan, USA.
JCI Insight ; 6(17)2021 09 08.
Статья в английский | MEDLINE | ID: covidwho-1413722
ABSTRACT
Neutrophil-mediated activation and injury of the endothelium play roles in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap-derived [NET-derived] histones) with polyanionic compounds has been suggested as a potential strategy for protecting the endothelium from such insults. Here, we report that the US Food and Drug Administration-approved polyanionic agent defibrotide (a pleiotropic mixture of oligonucleotides) directly engages histones and thereby blocks their pathological effects on endothelium. In vitro, defibrotide counteracted endothelial cell activation and pyroptosis-mediated cell death, whether triggered by purified NETs or recombinant histone H4. In vivo, defibrotide stabilized the endothelium and protected against histone-accelerated inferior vena cava thrombosis in mice. Mechanistically, defibrotide demonstrated direct and tight binding to histone H4 as detected by both electrophoretic mobility shift assay and surface plasmon resonance. Taken together, these data provide insights into the potential role of polyanionic compounds in protecting the endothelium from thromboinflammation with potential implications for myriad NET- and histone-accelerated disease states.
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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Polydeoxyribonucleotides / Thrombosis / Human Umbilical Vein Endothelial Cells / Fibrinolytic Agents Пределы темы: Животные / Люди / Мужчины Язык: английский Год: 2021 Тип: Статья Аффилированная страна: Jci.insight.149149

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Полный текст: Имеется в наличии Коллекция: Международные базы данных база данных: MEDLINE Основная тема: Polydeoxyribonucleotides / Thrombosis / Human Umbilical Vein Endothelial Cells / Fibrinolytic Agents Пределы темы: Животные / Люди / Мужчины Язык: английский Год: 2021 Тип: Статья Аффилированная страна: Jci.insight.149149