Diane Chiang

University of Michigan–Ann Arbor

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Jason S. Knight

University of Michigan–Ann Arbor

Alex A. Gandhi

University of Michigan–Ann Arbor

Jiandie D. Lin

University of Michigan–Ann Arbor

James H. Morrissey

University of Michigan–Ann Arbor

Hui Shi

Shanghai University of Sport

Stephanie A. Smith

University of Michigan–Ann Arbor

Yogendra Kanthi

National Heart Lung and Blood Institute

Evan A. Farkash

University of Michigan–Ann Arbor

Pei‐Suen Tsou

University of Michigan–Ann Arbor

Srilakshmi Yalavarthi

University of Michigan–Ann Arbor

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University of Michigan–Ann Arbor

Michigan United

Michigan Medicine

Center for Rheumatology

National Institutes of Health

Shanghai Jiao Tong University

Ministry of Agriculture and Rural Affairs

Regional West Medical Center

National Institute of Arthritis and Musculoskeletal and Skin Diseases

Scripps Research Institute

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Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

medRxiv (Cold Spring Harbor Laboratory) (2021)

Hui Shi Alex A. Gandhi Stephanie A. Smith Qiuyu Wang Diane Chiang

Neutrophil-mediated activation and injury of the endothelium play a role in the pathogenesis of diverse disease states ranging from autoimmunity to cancer to COVID-19. Neutralization of cationic proteins (such as neutrophil extracellular trap/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 FDA-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.

Defibrotide

Neutrophil Extracellular Traps

10.1101/2021.02.21.21252160

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Endothelium-protective, histone-neutralizing properties of the polyanionic agent defibrotide

JCI Insight (2021)

Hui Shi Alex A. Gandhi Stephanie A. Smith Qiuyu Wang Diane Chiang

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.

Defibrotide

Neutrophil Extracellular Traps

10.1172/jci.insight.149149

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Citations (29)