期刊
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
卷 11, 期 6, 页码 1020-1028出版社
WILEY-BLACKWELL
DOI: 10.1111/jth.12243
关键词
antithrombin; heparin; inflammation; ischemia; signal transduction
资金
- National Heart, Lung, and Blood Institute of the National Institutes of Health [HL 62565, HL 101917]
- American Heart Association [SDG0835169N, 12GRNT11620029]
- American Diabetes Association Basic Science [1-11-BS-92]
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)- and interleukin (IL)-6 in vivo by attenuating ischemia/reperfusion-induced JNK and NF-B 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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