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    Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice

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    Author
    Mukhopadhyay, S.
    Antalis, T.M.
    Nguyen, K.P.
    Date
    2017
    Journal
    Blood
    Publisher
    American Society of Hematology
    Type
    Article
    
    Metadata
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    See at
    https://doi.org/10.1182/blood-2016-07-727180
    Abstract
    Deep venous thrombosis (DVT) remains a common and serious cardiovascular problem with both fatal and long-term consequences. The consequences of DVT include the development of postthrombotic syndrome in 25% to 60% of DVT patients. Despite the clinical importance of venous thrombus resolution, the cellular and molecular mediators involved are poorly understood, and currently there is no molecular therapy to accelerate this process. Several lines of evidence suggest that a complex and interrelated array of molecular signaling processes are involved in the inflammatory vascular remodeling associated with the resolution of DVT. Here, we have identified a role for the tumor suppressor gene p53 inregulating venous thrombus resolution. Using the stasis model of venous thrombosis and resolution in mice, we found that genetic deficiency of p53 or pharmacologic inhibition by pifithrin impairs thrombus resolution and is associated with increased fibrosis and altered expression of matrix metalloproteinase-2. The effect of p53 loss was mediated by cells of themyeloid lineage, resulting in enhanced polarization of the cytokine milieu toward an M1-like phenotype. Furthermore, augmentation of p53 activity using the pharmacological agonist of p53, quinacrine, accelerates venous thrombus resolution in a p53-dependent manner, even after establishment of thrombosis. Together, these studies define mechanisms by which p53 regulates thrombus resolution by increasing inflammatory vascular remodeling of venous thrombi in vivo, and the potential therapeutic application of a p53 agonist as a treatment to accelerate this process in patients with DVT. Copyright 2017 by The American Society of Hematology.
    Sponsors
    This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute grant R01HL083917 (R.S.), and also in part by National Institutes of Health, National Cancer Institute grant T32 CA154274-01 (M.H.H.) and award number 1I01BX001921 (T.M.A.) from the Biomedical Laboratory Research & Development Service of the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development.
    Keyword
    vascular biology
    Phagocytes
    Granulocytes
    Myelopoiesis
    Thrombosis
    Hemostasis
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85021080224&doi=10.1182%2fblood-2016-07-727180&partnerID=40&md5=c45ea60ceb692e3b4e5b0e826989d257; http://hdl.handle.net/10713/11313
    ae974a485f413a2113503eed53cd6c53
    10.1182/blood-2016-07-727180
    Scopus Count
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    UMB Open Access Articles 2017

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