Antithrombin is protective against myocardial ischemia and reperfusion injury

Authors

  • J. Wang,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • Y. Wang,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • J. Wang,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • J. Gao,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • C. Tong,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • C. Manithody,

    1. Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
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  • J. Li,

    1. Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • A. R. Rezaie

    Corresponding author
    1. Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO, USA
    • Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY, USA
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  • Manuscript handled by: W. Aird
  • Final decision: D. Lane, 17 March 2013

Correspondence: Alireza R. Rezaie, Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA.

Tel.: +1 314 977 9240; fax: +1 314 977 9205.

E-mail: rezaiear@slu.edu

and

Ji Li, Department of Pharmacology and Toxicology, University at Buffalo-SUNY, Buffalo, NY 14214, USA.

Tel.: +1 716 829 5711; fax: +1 716 829 2801.

E-mail: jli23@buffalo.edu

Summary

Background

Antithrombin (AT) is a plasma serpin inhibitor that regulates the proteolytic activity of procoagulant proteases of the clotting cascade. In addition to its anticoagulant activity, AT also possesses potent anti-inflammatory properties.

Objectives

The objective of this study was to investigate the anti-inflammatory activity of wild-type AT (AT-WT) and a reactive centre loop mutant of AT (AT-RCL) which is not capable of inhibiting thrombin.

Methods

The cardioprotective activities of AT-WT and AT-RCL were monitored in a mouse model of ischemia/reperfusion (I/R) injury in which the left anterior descending coronary artery was occluded and then released.

Results

We demonstrate that AT markedly reduces myocardial infarct size by a mechanism that is independent of its anticoagulant activity. Thus, AT-RCL attenuated myocardial infarct size to the same extent as AT-WT in this acute injury model. Further studies revealed that AT binds to vascular heparan sulfate proteoglycans via its heparin-binding domain to exert its protective activity as evidenced by the therapeutic AT-binding pentasaccharide (fondaparinux) abrogating the cardioprotective activity of AT and a heparin-site mutant of AT exhibiting no cardioprotective property. We further demonstrate that AT up-regulates the production of prostacyclin in myocardial tissues and inhibits expression of pro-inflammatory cytokines tumor necrosis factor (TNF)-α and interleukin (IL)-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-κB signaling pathways.

Conclusions

The present results suggest that both AT and the non-anticoagulant AT-RCL, through their anti-inflammatory signaling effects, elicit potent cardioprotective responses. Thus, AT may have therapeutic potential for treating cardiac I/R injury.

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