title: Antithrombin is protective against myocardial ischemia and reperfusion injury.
abstract: 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.
  
  
  OBJECTIVE
  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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo-SUNY, Buffalo, NY 14214, USA.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: J
authors.initials: J
authors.lastname: Gao
authors.forename: C
authors.initials: C
authors.lastname: Tong
authors.forename: C
authors.initials: C
authors.lastname: Manithody
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.forename: A R
authors.initials: AR
authors.lastname: Rezaie
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry*; D002316:Cardiotonic Agents / Q000737:chemistry; D000077425:Fondaparinux; D006493:Heparin / Q000737:chemistry; D007249:Inflammation; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D011134:Polysaccharides / Q000737:chemistry; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology*; D015398:Signal Transduction; D013917:Thrombin / Q000037:antagonists & inhibitors; D019210:Troponin I / Q000737:chemistry; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; D000991:Antithrombins; D002316:Cardiotonic Agents; D015850:Interleukin-6; D016328:NF-kappa B; D011134:Polysaccharides; D019210:Troponin I; D014409:Tumor Necrosis Factor-alpha; D006493:Heparin; D048670:MAP Kinase Kinase 4; D013917:Thrombin; D000077425:Fondaparinux
keywords: antithrombin; heparin; inflammation; ischemia; signal transduction