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Thromb Haemost. 2015 Feb;113(2):338-49. doi: 10.1160/TH14-04-0360. Epub 2014 Sep 18.

Antithrombin up-regulates AMP-activated protein kinase signalling during myocardial ischaemia/reperfusion injury.

Author information

1
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.
2
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.

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.

PMID:
25230600
PMCID:
PMC4308562
DOI:
10.1160/TH14-04-0360
[Indexed for MEDLINE]
Free PMC Article

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