Abstract 9145: Tyrosine 705 Phosphorylation of STAT3 is Causally Involved in Cardioprotection by Ischemic Postconditioning in Pigs

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In mice, the signal transducer and activator of transcription (STAT) 3 is causally involved in protection by ischemic postconditioning (PoCo) against myocardial infarction. However, signal transduction in rodents differs from that in larger mammals. We have now determined the impact of PoCo on STAT3 activation/phosphorylation in pig hearts, which more closely resemble human hearts in size, coronary anatomy, heart rate, and infarct development. Anesthetized pigs were subjected to 90 min low flow ischemia and 120 min reperfusion, initiated with either PoCo (six cycles of 20 s reperfusion/re-occlusion, n=8) or immediate full reperfusion (IFR, n=8). Eight additional pigs were treated with the JAK/STAT inhibitor AG490 (9 µg/kg/min i.c.; 10 min before ischemia until the end of reperfusion; AG-PoCo n=4, AG-IFR n=4). Myocardial biopsies were taken at baseline, 85 min ischemia and 10, 30, and 120 min reperfusion. STAT3 phosphorylation and total STAT3 protein were quantified by Western blot analysis. Area at risk (AAR) and regional myocardial blood flow (microspheres) during ischemia were not different between groups. PoCo reduced infarct size (TTC staining) from 38±2 to 26±3 % of the AAR (p<0.05). AG490 abolished this infarct size reduction (AG-IFR: 36±4 vs. AG-PoCo: 36±1 % of AAR). STAT3 tyr 705 phosphorylation normalized to total STAT3 protein (Table 1) increased during ischemia/reperfusion; in pigs subjected to PoCo the STAT3 tyr 705 phosphorylation was even greater than with IFR (p<0.05, ANOVA). STAT3 ser 727 phosphorylation was increased with PoCo and IFR to a similar extent. AG490 attenuated the increases in STAT3 phosphorylation in both groups to values below those with IFR and PoCo. Conclusion: In pigs, PoCo further increases STAT3 tyr 705 phosphorylation and protects the myocardium from infarction. AG490 attenuates the STAT3 tyr 705 activation at reperfusion and abolishes PoCo's protection. Thus, in pigs STAT3 is causally involved in cardioprotection by PoCo.