Leptin-induced protection against myocardial ischemia-reperfusion (I/R) injury involves activation of the Reperfusion Injury Salvage Kinase (RISK) pathway and inhibition of the mitochondrial permeability transition pore (MPTP). Recently published data indicate that the JAK/STAT pathway, which mediates the metabolic actions of leptin, also plays a pivotal role in cardioprotection. Consequently, we considered the possibility that JAK/STAT signaling linked to the MPTP may be involved in modulating the cardioprotective actions of leptin. Employing rat in vitro models (Langendorff perfused hearts and cardiomyocytes) of I/R injury we investigated the actions of leptin (10nM), administered at reperfusion, in the presence or absence of the JAK2 inhibitor, AG490 (5 μμM). Leptin reduced infarct size significantly (control, 60.05±7.41% vs leptin, 29.9±3.24%, p<0.05), protection being abolished by AG490. Harvesting hearts at different time points revealed that leptin caused a 171% (p<0.001) increase (versus time-matched control hearts) in tyrosine-705/STAT3 phosphorylation at 2.5 min reperfusion, however, increases were not seen at 5, 10, 15 or 30 min reperfusion. Contrasting with STAT3, serine-473/Akt phosphorylation was not significantly increased until 15 min into the reperfusion phase (140%, p<0.05). AG490 blocked the leptin-induced rise in STAT3 phosphorylation seen with hearts reperfused for 2.5 min but did not influence serine-473/Akt phosphorylation at 15 min. Leptin reduced MPTP opening (p<0.001) which was blocked by AG490. This is the first study to yield evidence that JAK/STAT signaling linked to the MPTP may play a role in leptin-induced cardioprotection. Under the experimental conditions employed we conclude that STAT3 phosphorylation may occur earlier during reperfusion than that of Akt. Further investigation into the interactions between these signalling pathways and their link to MPTP opening in the setting of I/R injury is, however, required.
- ischemia-reperfusion injury
- JAK/STAT signalling
- Copyright © 2010, American Journal of Physiology - Heart and Circulatory Physiology