Abstract 11738: AMP-Activated Protein Kinase Signaling Mediates the Cardioprotective Effect of Antithrombin Against Myocardial Ischemia and Reperfusion Injury
Introduction: Antithrombin (AT) is an endogenous protein of the serpin superfamily involved in regulation of the proteolytic activity of the serine proteases of the coagulation system. In addition to its anticoagulant function, AT also exhibits an anti-inflammatory and cardioprotective function when it binds to distinct heparin sulfate proteoglycans (HSPG) on vascular endothelial cells. The energy sensor AMP-activated protein kinase (AMPK) is known to play an important cardioprotective role during myocardial ischemia and reperfusion (I/R).
Hypothesis: The cardioprotective function of AT may be through activation of AMPK by which modulates the substrate metabolism.
Methods: The cardioprotective activities of wild-type (WT) AT and its two recombinant derivatives one having high affinity and the other no affinity for heparin were evaluated in an acute in vivo regional ischemia/reperfusion (30 min/24 hours) injury model in which the left anterior descending coronary artery (LAD) was occluded and released. The serpin derivatives were given 5 min before reperfusion. Langendroff perfused heart system was used to approach an ex vivo global ischemia model.
Results: AT-WT can activate the protective AMPK signaling pathway in both in vivo and ex vivo conditions. Blocking AMPK activity by using AMPK kinase dead (KD) transgenic mice, the cardioprotective function of AT against I/R damage was abolished. The AT derivative having high affinity for heparin was more effective in activating AMPK but the derivative lacking any affinity for heparin was inactive in eliciting AMPK-dependent cardioprotective activity. Moreover, the AMPK-dependent activity of AT significantly inhibited I/R-induced inflammatory c-Jun N-terminal protein kinase (JNK) pathway. In the ex vivo working heart perfusion system, the further studies revealed that the AMPK activity of AT also modulates cardiac substrate metabolism by increasing glucose oxidation but inhibiting fatty acid oxidation during I/R.
Conclusions: These results suggest that AT binds to heparin sulfate proteoglycans to invoke a cardioprotective function through triggering cardiac AMPK activation, thereby attenuating JNK inflammatory signaling pathways and modulating substrate metabolism during I/R.
Author Disclosures: Y. Ma: None. J. Wang: None. J. Gao: None. H. Yang: None. W. Sun: None. X. Chen: None. Y. Wang: None. A.R. Rezaie: None. J. Li: None.
This research has received full or partial funding support from the American Heart Association.
- © 2014 by American Heart Association, Inc.