NADPH oxidase 1 is a novel pharmacological target for the development of an antiplatelet drug without bleeding side effects.

Autor: Vara D; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Tarafdar A; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Celikag M; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Patinha D; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Gulacsy CE; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK., Hounslea E; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK., Warren Z; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Ferreira B; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Koeners MP; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK., Caggiano L; Department of Pharmacy and Pharmacology, University of Bath, Bath, UK., Pula G; Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2020 Oct; Vol. 34 (10), pp. 13959-13977. Date of Electronic Publication: 2020 Aug 26.
DOI: 10.1096/fj.202001086RRR
Abstrakt: Growing evidence supports a central role of NADPH oxidases (NOXs) in the regulation of platelets, which are circulating cells involved in both hemostasis and thrombosis. Here, the use of Nox1 -/- and Nox1 +/+ mice as experimental models of human responses demonstrated a critical role of NOX1 in collagen-dependent platelet activation and pathological arterial thrombosis, as tested in vivo by carotid occlusion assays. In contrast, NOX1 does not affect platelet responses to thrombin and normal hemostasis, as assayed in tail bleeding experiments. Therefore, as NOX1 inhibitors are likely to have antiplatelet effects without associated bleeding risks, the NOX1-selective inhibitor 2-acetylphenothiazine (2APT) and a series of its derivatives generated to increase inhibitory potency and drug bioavailability were tested. Among the 2APT derivatives, 1-(10H-phenothiazin-2-yl)vinyl tert-butyl carbonate (2APT-D6) was selected for its high potency. Both 2APT and 2APT-D6 inhibited collagen-dependent platelet aggregation, adhesion, thrombus formation, superoxide anion generation, and surface activation marker expression, while responses to thrombin or adhesion to fibrinogen were not affected. In vivo administration of 2APT or 2APT-D6 led to the inhibition of mouse platelet aggregation, oxygen radical output, and thrombus formation, and carotid occlusion, while tail hemostasis was unaffected. Differently to in vitro experiments, 2APT-D6 and 2APT displayed similar potency in vivo. In summary, NOX1 inhibition with 2APT or its derivative 2APT-D6 is a viable strategy to control collagen-induced platelet activation and reduce thrombosis without deleterious effects on hemostasis. These compounds should, therefore, be considered for the development of novel antiplatelet drugs to fight cardiovascular diseases in humans.
(© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
Databáze: MEDLINE
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