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    NADPH oxidases are required for full platelet activation in vitro and thrombosis in vivo but dispensable for plasma coagulation and hemostasisand apoptosis

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    Authors
    Vara, D.
    Mailer, R. K.
    Tarafdar, Anuradha
    Wolska, N.
    Heestermans, M.
    Konrath, S.
    Spaeth, M.
    Renné, T.
    Schröder, K.
    Pula, G.
    Affiliation
    Institute of Biomedical and Clinical Science, University of Exeter Medical School, United Kingdom
    Issue Date
    2020
    
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    Abstract
    Objective: Using 3KO (triple NOX [NADPH oxidase] knockout) mice (ie, NOX1-/-/NOX2-/-/NOX4-/-), we aimed to clarify the role of this family of enzymes in the regulation of platelets in vitro and hemostasis in vivo. Approach and Results: 3KO mice displayed significantly reduced platelet superoxide radical generation, which was associated with impaired platelet aggregation, adhesion, and thrombus formation in response to the key agonists collagen and thrombin. A comparison with single-gene knockouts suggested that the phenotype of 3KO platelets is the combination of the effects of the genetic deletion of NOX1 and NOX2, while NOX4 does not show any significant function in platelet regulation. 3KO platelets displayed significantly higher levels of cGMP-a negative platelet regulator that activates PKG (protein kinase G). The inhibition of PKG substantially but only partially rescued the defective phenotype of 3KO platelets, which are responsive to both collagen and thrombin in the presence of the PKG inhibitors KT5823 or Rp-8-pCPT-cGMPs, but not in the presence of the NOS (NO synthase) inhibitor L-NG-monomethyl arginine. In vivo, triple NOX deficiency protected against ferric chloride-driven carotid artery thrombosis and experimental pulmonary embolism, while hemostasis tested in a tail-tip transection assay was not affected. Procoagulatory activity of platelets (ie, phosphatidylserine surface exposure) and the coagulation cascade in platelet-free plasma were normal. Conclusions: This study indicates that inhibiting NOXs has strong antithrombotic effects partially caused by increased intracellular cGMP but spares hemostasis. NOXs are, therefore, pharmacotherapeutic targets to develop new antithrombotic drugs without bleeding side effects.
    Citation
    Vara D, Mailer RK, Tarafdar A, Wolska N, Heestermans M, Konrath S, et al. NADPH Oxidases Are Required for Full Platelet Activation In Vitro and Thrombosis In Vivo but Dispensable for Plasma Coagulation and Hemostasis. Arterioscler Thromb Vasc Biol. 2020:ATVBAHA120315565.
    Journal
    Arteriosclerosis, thrombosis, and vascular biology
    URI
    http://hdl.handle.net/10541/623659
    DOI
    10.1161/atvbaha.120.315565
    PubMed ID
    33267663
    Additional Links
    https://dx.doi.org/10.1161/atvbaha.120.315565
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1161/atvbaha.120.315565
    Scopus Count
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    All Paterson Institute for Cancer Research

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