Across-Species Transfer of Protection by Remote Ischemic Preconditioning with Species-Specific Myocardial Signal Transduction by RISK and SAFE Pathways
Rationale: Reduction of myocardial infarct size (IS) by remote ischemic preconditioning (RIPC), i.e. cycles of ischemia/reperfusion in an organ remote from the heart prior to sustained myocardial ischemia/reperfusion, was confirmed in all species so far, including humans.
Objective: To identify myocardial signal transduction of cardioprotection by RIPC.
Methods and Results: Anesthetized pigs were subjected to RIPC (4x5/5 min hindlimb ischemia/reperfusion) or placebo (PLA) prior to 60/180 min coronary occlusion/reperfusion. Phosphorylation of AKT, ERK1/2 (RISK pathway), and STAT3 (SAFE pathway) in the risk area were determined by Western blot. Wortmannin/U0126 or AG490 were used for pharmacological RISK or SAFE blockade, respectively. Plasma sampled after RIPC or PLA, respectively, was transferred to isolated bioassay rat hearts subjected to 30/120 min global ischemia/reperfusion. RIPC reduced IS in pigs to 16±11% vs. 43±11% in PLA (% risk area; mean±SD; p<0.05). RIPC increased phosphorylation of STAT3 at early reperfusion, and AG490 abolished protection whereas RISK blockade did not. STAT5 phosphorylation was decreased at early reperfusion in both, RIPC and PLA. In isolated rat hearts, pig plasma taken after RIPC reduced IS (25±5% of ventricular mass vs. 38±5% in PLA; p<0.05) and activated both, RISK and SAFE. RISK or SAFE blockade abrogated this protection.
Conclusions: Cardioprotection by RIPC in pigs causally involves activation of STAT3 but not of RISK. Protection can be transferred with plasma from pigs to isolated rat hearts where both activation of RISK and SAFE are causally involved. The myocardial signal transduction of RIPC is the same as that of ischemic postconditioning.
- remote ischemic preconditioning
- myocardial infarction
- myocardial ischemia
- signal transduction
- Received May 19, 2015.
- Revision received June 4, 2015.
- Accepted June 9, 2015.