title: Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury.
abstract: Antithrombin (AT) is a protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. AT is known to exhibit anti-inflammatory and cardioprotective properties when it binds to heparan sulfate proteoglycans (HSPGs) on vascular cells. AMP-activated protein kinase (AMPK) plays an important cardioprotective role during myocardial ischaemia and reperfusion (I/R). To determine whether the cardioprotective signaling function of AT is mediated through the AMPK pathway, we evaluated the cardioprotective activities of wild-type AT and its two derivatives, one having high affinity and the other no affinity for heparin, in an acute I/R injury model in C57BL/6J mice in which the left anterior descending coronary artery was occluded. The serpin derivatives were given 5 minutes before reperfusion. The results showed that AT-WT can activate AMPK in both in vivo and ex vivo conditions. Blocking AMPK activity abolished the cardioprotective function of AT against I/R injury. The AT derivative having high affinity for heparin was more effective in activating AMPK and in limiting infraction, but the derivative lacking affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Activation of AMPK by AT inhibited the inflammatory c-Jun N-terminal protein kinase (JNK) pathway during I/R. Further studies revealed that the AMPK activity induced by AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R. These results suggest that AT binds to HSPGs on heart tissues to invoke a cardioprotective function by triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signalling pathways and modulating substrate metabolism during I/R.
authors.forename: Yina
authors.initials: Y
authors.lastname: Ma
authors.forename: Jinli
authors.initials: J
authors.lastname: Wang
authors.forename: Junjie
authors.initials: J
authors.lastname: Gao
authors.forename: Hui
authors.initials: H
authors.lastname: Yang
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wang
authors.forename: Chandrashekhara
authors.initials: C
authors.lastname: Manithody
authors.affiliation: Ji Li, PhD, Department of Pharmacology and Toxicology, State University of New York at Buffalo, Buffalo, NY 14214, USA, Tel.: +1 716 829 5711, Fax: +1 716 829 2801, E-mail: jli23@buffalo.edu.
authors.forename: Ji
authors.initials: J
authors.lastname: Li
authors.affiliation: Alireza R. Rezaie, PhD, 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.
authors.forename: Alireza R
authors.initials: AR
authors.lastname: Rezaie
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D000991:Antithrombins / Q000737:chemistry*; D002316:Cardiotonic Agents / Q000737:chemistry; D005227:Fatty Acids / Q000737:chemistry; D005947:Glucose / Q000737:chemistry; D006321:Heart / Q000502:physiology; D006493:Heparin / Q000737:chemistry; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007249:Inflammation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology*; D015428:Myocardial Reperfusion Injury / Q000473:pathology*; D010100:Oxygen / Q000737:chemistry; D010539:Permeability; D010641:Phenotype; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D002316:Cardiotonic Agents; D005227:Fatty Acids; D006493:Heparin; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D010100:Oxygen