Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice
PublisherAmerican Society of Hematology
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AbstractDeep 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.
SponsorsThis 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.
Identifier to cite or link to this itemhttps://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
- Differential transcriptional activation of matrix metalloproteinase-2 and membrane type-1 matrix metalloproteinase by experimental deep venous thrombosis and thrombin.
- Authors: Dahi S, Lee JG, Lovett DH, Sarkar R
- Issue date: 2005 Sep
- Serpins in Venous Thrombosis and Venous Thrombus Resolution.
- Authors: Mukhopadhyay S, Johnson TA, Sarkar R, Antalis TM
- Issue date: 2018
- Alterations in macrophage phenotypes in experimental venous thrombosis.
- Authors: Gallagher KA, Obi AT, Elfline MA, Hogikyan E, Luke CE, Henke S, Coleman D, Henke PK
- Issue date: 2016 Oct
- Inflammation modulates murine venous thrombosis resolution in vivo: assessment by multimodal fluorescence molecular imaging.
- Authors: Ripplinger CM, Kessinger CW, Li C, Kim JW, McCarthy JR, Weissleder R, Henke PK, Lin CP, Jaffer FA
- Issue date: 2012 Nov
- Enhanced venous thrombus resolution in plasminogen activator inhibitor type-2 deficient mice.
- Authors: Siefert SA, Chabasse C, Mukhopadhyay S, Hoofnagle MH, Strickland DK, Sarkar R, Antalis TM
- Issue date: 2014 Oct