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Infarct Size Reduction by Remote Ischemic Perconditioning in Pigs Requires Activation of the SAFE but not the RISK Pathway
Author(s) -
Kleinbongard Petra,
Gent Sabine,
Skyschally Andreas,
Heusch Gerd
Publication year - 2016
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.30.1_supplement.1207.1
Subject(s) - medicine , cardioprotection , ischemia , ischemic preconditioning , cardiology , reperfusion injury , ligation , myocardial infarction , evans blue , coronary occlusion , anesthesia
Brief episodes of ischemia/reperfusion in a tissue or organ remote from the heart can reduce myocardial infarct size following sustained severe ischemia/reperfusion. Such remote conditioning can be induced before (pre‐) or during (per‐) myocardial ischemia, and protection by remote conditioning was confirmed in all species tested so far, including humans. In pigs, cardioprotection by remote preconditioning causally involves the activation of the survival activating factor enhancement (SAFE) pathway, whereas the activation of the reperfusion injury salvage kinase (RISK) pathway is not necessary (Circ Res 2015;117:279–88). We have now used a clinically relevant pig model to identify the myocardial signal transduction of remote ischemic perconditioning (RPERC). Anesthetized open‐chest pigs were subjected to 60 minutes occlusion of the left anterior descending coronary artery (LAD), followed by 180 minutes reperfusion. RPERC (n=10) was induced by 4×5/5 minutes hindlimb ischemia/reperfusion during the last 40 minutes of ischemia. Placebo pigs (PLA; n=10) without hindlimb ischemia/reperfusion served as controls. Regional myocardial blood flow was measured with colored microspheres. The area at risk (AAR) was delineated by atrial injection of 5 ml blue dye after LAD re‐ligation at the end of the experiment. Infarcted tissue was demarcated by TTC staining and calculated as % of the AAR. Myocardial biopsies were taken before LAD occlusion (baseline) and at 10 min reperfusion from the AAR to determine changes in the phosphorylation of protein kinase B and extracellular signal‐regulated kinase 1/2 as the main RISK pathway components and the phosphorylation of signal transducer and activator of transcription 3 as the central SAFE pathway component by Western blot. In additional experiments, RPERC was performed in the presence of either RISK‐blockade (Wortmannin/U0126; n=4) or SAFE‐blockade (AG490; n=4). Residual myocardial blood flow during ischemia and AAR were not different between groups. RPERC reduced infarct size to 16±10% vs. 42±10% in PLA (mean±SD; p<0.05; t‐test). RPERC increased the phosphorylation of STAT3 at 10 min reperfusion (p<0.05), whereas PLA did not. The SAFE‐blockade abolished both, the increased phosphorylation of STAT3 and the protection by RPERC (infarct size 36±5%; n.s. vs. PLA). In both groups phosphorylation of RISK was increased from baseline to 10 minutes reperfusion. RISK‐blockade abolished this increase, but RPERC still protected the myocardium (infarct size 8±1%; p<0.05 vs. PLA). The present experiments confirm the causal involvement of STAT3 activation during cardioprotection by RPERC in pigs, whereas an activation of RISK components is not involved. Thus, cardioprotection by RPERC is characterized by the same signal transduction pattern as that of remote ischemic preconditioning and local ischemic postconditioning.