Coronary effluent from a preconditioned heart activates the JAK-STAT pathway and induces cardioprotection in a donor heart

Preconditioning ( PC) protects against ischemia-reperfusion (I/R) injury via the activation of the JAK-STAT pathway. We hypothesized that the mediators responsible for PC can be transferred to naive myocardium through the coronary effluent. Langendorff-perfused hearts from male Sprague-Dawley rats were randomized to paired donor/acceptor protocols with or without PC in the presence or absence of the JAK-2 inhibitor AG-490 ( n = 6 for each group). Warmed, oxygenated coronary effluent collected during the reperfusion phases of PC ( 3 cycles of 5 min ischemia and 5 min reperfusion) was administered to acceptor hearts. The hearts were then subjected to 30 min ischemia and 40 min reperfusion. The left ventricles were analyzed for phosphorylated ( p) STAT-1, pSTAT-3, Bax, Bcl, Bcl-XL/Bcl-2-associated protein ( BAD), and caspase-3 expression by Western blot. A separate group of hearts ( n = 6) was analyzed for STAT activation immediately after the transfer of the PC effluent ( no I-R). Baseline cardiodynamics were not different among the groups. End-reperfusion maximal change in pressure over time ( + dP/dt(max)) was significantly ( P < 0.05) improved in acceptor PC ( 3,637 +/- 199 mmHg/s) and donor PC ( 4,304 +/- 347 mmHg/s) hearts over non-PC donor ( 2,020 +/- 363 mmHg/s) and acceptor ( 2,624 +/- 345 mmHg/s) hearts. Similar differences were seen for minimal change in pressure over time ( -dP/dt(min)). STAT-3 activation was significantly increased in donor and acceptor PC hearts compared with non-PC hearts. Conversely, pSTAT-1 and Bax expression was decreased in donor and acceptor PC hearts compared with non-PC hearts. No differences in Bcl, BAD, or caspase-3 expression were observed. Treatment with AG-490 attenuated the recovery of +/- dP/dt in acceptor PC hearts and significantly reduced pSTAT-3 expression. The PC coronary effluent activates JAK-STAT signaling, limits apoptosis, and protects myocardial performance from I/R injury.