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Infarct size reduction by remote ischemic perconditioning and humoral transfer of protection across species
Author(s) -
Kleinbongard Petra,
Lieder Helmut,
Gent Sabine,
Skyschally Andreas,
Heusch Gerd
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.845.2
Subject(s) - cardioprotection , medicine , cardiology , ischemia , myocardial infarction , ischemic preconditioning
Brief episodes of ischemia/reperfusion (I/R) in a tissue or organ remote from the heart reduce infarct size after sustained severe myocardial I/R in all species tested so far, including humans. Remote ischemic conditioning can be induced before (pre‐), during ( per‐ ) or following (post‐)myocardial ischemia. The signal transfer from the periphery to the heart and the signal transduction of remote ischemic per conditioning (RPERC) within the myocardium, however, are still unclear in detail. The objective of the present study was to identify humoral signal transfer and myocardial signal transduction of cardioprotection by RPERC. Anesthetized open‐chest pigs were subjected to 60 min occlusion of the left anterior descending coronary artery (LAD) and 180 min reperfusion (n=10, placebo PLA). RPERC (n=10) was induced by 4×5/5 min hindlimb I/R during the final 40 min of LAD occlusion. Arterial blood was sampled after PLA or RPERC, respectively. Diluted plasma (1:5) was infused into isolated rat hearts and diluted plasma dialysate (1:5; <12–14kDa) into isolated mouse hearts. The rodent hearts were then subjected to 30/120 min global I/R. RPERC was also performed in the presence of either Akt+ERK‐blockade (Wortmannin/U0126; n=4) or STAT3‐blockade (AG490; n=4), respectively. The infarction was demarcated with TTC and calculated as % of area at risk (AAR) in pig hearts or % of ventricular mass in rodent hearts, respectively. In pigs, myocardial biopsies were taken at baseline and at 10 min reperfusion from the AAR, and the phosphorylation (phospho) of Akt, ERK and STAT3 was determined by Western blot. RPERC reduced infarct size and increased the phosphorylation of STAT3 at 10 min reperfusion vs. PLA. STAT3‐blockade abolished STAT3 phosphorylation and infarct size reduction, whereas Akt+ERK‐blockade abolished Akt and ERK activation, but not infarct size reduction (see Figure). In isolated rat and mouse hearts, pig plasma/plasma dialysate taken after PERC reduced infarct size (rat: 22±2% versus 35±2% in PLA; mouse: 31±3% versus 50±4% in PLA; P<0.01 each). In conclusion, in pigs STAT3 activation is required for cardioprotection by RPERC, whereas activation of Akt and ERK is not. Protection can be transferred with plasma and plasma dialysate <12–14kDa from pigs to isolated rodent hearts. In pigs, the cardioprotection by RPERC is characterized by the same signal transduction pattern as that by remote ischemic preconditioning ( Circ Res 2015;117:279–88) and local ischemic postconditioning (Circ Res 2011;109:1302–8). Support or Funding Information German Research Foundation (DFG): SFB 1116 B08A: Infarct size in pig hearts. B: Phosphorylation of signal transducer and activator of transcription 3 (STAT3) at tyr705 (survival activating factor enhancement [SAFE] pathway) and protein kinase B (Akt) at ser473 and extracellular signal–regulated kinase 1/2 (ERK) at thr202/tyr204 (reperfusion injury salvage kinase [RISK] pathway) in pig myocardium from the area at risk, taken at baseline (open bars) and at 10 min reperfusion (filled bars).