Isoflurane preconditioning and propofol postconditioning synergistically enhance STAT3 activation and reduce postischemic myocardial infarction in rats

Abstract

BACKGROUND: Isoflurane preconditioning (IsoPC) and propofol anaesthesia have been shown to synergistically attenuate myocardial reperfusion injury in humans (1), but the underlying mechanism is unclear. Recent studies show that the JAK/STAT3 pathway plays an essential role both in cardiac ischemic preconditioning (2) and postconditioning (3). We, therefore, hypothesized that IsoPC and propofol postconditioning (PPostC) may synergistically activate signal transducer and activator of transcription 3 (STAT3) and thus facilitate cardioprotection. METHODS: With ethics approval, adult male SD-rats were subjected to myocardial ischemia-reperfusion injury by occluding the left coronary artery for 30 min followed by 120 min of reperfusion. Rats (n=5-6 per group) were either untreated (control), treated with IsoPC (8% emulsified isoflurane at 2 ml/ kg) for 10 min before inducing ischemia, with intravenous propofol starting from 5 min before reperfusion until 10 min of reperfusion (PPostC), or a combination of IsoPC and PPostC (group IP). At the end of reperfusion, myocardial infarct size (IS) was assessed by triphenyltetrazolium staining and left ventricular tissue was processed for total STAT3 protein and its phosphorylation status at site Tyr705 (p-STAT3) by Western blotting analysis. Data are expressed as mean +/- SEM and were analyzed with ANOVA. RESULTS: Postischemic myocardial IS expressed as percentage of area at risk was 45±7% in the control group and was moderately but significantly reduced by either IsoPC (37±5%) or PPostC (39±3%) (all P<0.05 vs. control). IsoPC and PPostC combination further reduced IS to 20±3% (P<0.01 group IP vs. all other groups). Myocardial total STAT3 protein expression did not significantly differ among groups. The levels of p-STAT3 in the IsoPC and PPostC groups were, respectively, about 1.2-fold and 1.3-fold of that in the control group, but these differences did not reach statistical significance. However, p-STAT3 protein expression in group IP was 1.9-fold of that in the control group (P<0.01 vs. control). CONCLUSIONS: Enhancement of STAT3 phosphorylation/activation may represent an important mechanism by which IsoPC and PPostC synergistically attenuate postischemic myocardial infarct size.