Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction

Authors

  • J. Gabre,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • C. Chabasse,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • C. Cao,

    1. Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
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  • S. Mukhopadhyay,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • S. Siefert,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • Y. Bi,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • S. Netzel-Arnett,

    1. Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
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  • R. Sarkar,

    1. Center for Vascular and Inflammatory Diseases, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
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  • L. Zhang

    Corresponding author
    1. Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA
    • Correspondence: Li Zhang, Center for Vascular and Inflammatory Diseases, Department of Physiology, University of Maryland School of Medicine, 800 W Baltimore Street, Baltimore, MD 21201, USA.

      Tel.: +1 410 706 8040; fax: +1 410 706 8121.

      E-mail: lizhang@som.umaryland.edu

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  • See also Deguchi H, Elias DJ, Griffin JH. Gain in translation: heme oxygenase-1 induced by activated protein C promotes thrombus resolution. This issue, pp 90–2.
  • Manuscript handled by: W. Ruf
  • Final decision: P. H. Reitsma, 22 September 2013

Summary

Background

Thrombus resolution is a complex process that involves thrombosis, leukocyte-mediated thrombolysis, and the final resolution of inflammation. Activated protein C (APC) is an anticoagulant that also possesses immunoregulatory activities.

Aim

In this study, we sought to examine the effects of APC administration on thrombus resolution using a mouse model of deep vein thrombosis by ligating the inferior vena cava (IVC).

Methods

The IVCs of C57BL/6 mice were ligated. Beginning on day 4 post IVC ligation, mice were injected intraperitoneally daily with APC, APC plus an heme oxygenase-1 (HO-1) inhibitor Sn-protoporphyrin IX (SnPP), SnPP alone, or vehicle control. At different time points following surgery, the thrombus-containing IVCs were weighed and then analyzed by use of biochemical assays and histology.

Results

Venous thrombi reached maximum size on day 4 post ligation. The APC-treated group exhibited a significant reduction in thrombus weights on day 12 but not on day 7 compared with control mice. The enhanced thrombus resolution in APC-treated mice correlated with an increased HO-1 expression and a reduced interleukin-6 production. No significant difference was found in urokinase-type plasminogen activator, plasminogen activator inhibitor-1, or matrix metalloproteinase-2 and -9 between APC-treated and control mice. Coinjection of the HO-1 inhibitor SnPP abolished the ability of APC to enhance thrombus resolution.

Conclusions

Our data show that APC enhances the resolution of existing venous thrombi via a mechanism that is in part dependent on HO-1, suggesting that APC could be used as a potential treatment for patients with deep vein thrombosis to accelerate thrombus resolution.

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