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

Subhradip Mukhopadhyay, Toni M. Antalis, Khanh P. Nguyen, Mark H. Hoofnagle and Rajabrata Sarkar

Key points

  • Endogenous p53 within myeloid cells regulates venous thrombus resolution, intra-thrombus macrophage polarization and fibrosis.

  • The p53 agonist quinacrine accelerates resolution of established venous thrombus, a potential translational benefit in patients with DVT.

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 post-thrombotic syndrome (PTS) in 25-60% 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 in regulating 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 the metalloproteinase MMP-2. The effect of p53 loss was mediated by cells of the myeloid lineage, resulting in enhanced polarization of the cytokine milieu towards an M1-like phenotype. Further, 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.

  • Submitted July 11, 2016.
  • Accepted March 1, 2017.