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Antithrombin is protective against myocardial ischemia and reperfusion injury
Author(s) -
Wang J.,
Wang Y.,
Wang J.,
Gao J.,
Tong C.,
Manithody C.,
Li J.,
Rezaie A. R.
Publication year - 2013
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12243
Subject(s) - pharmacology , serpin , heparin , antithrombin , proinflammatory cytokine , reperfusion injury , ischemia , in vivo , chemistry , medicine , coagulation , proteases , inflammation , biochemistry , enzyme , biology , microbiology and biotechnology , gene
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.