Leptin-induced protection against
myocardial ischemia-reperfusion (I/R) injury involves the activation of the
reperfusion injury salvage
kinase pathway, incorporating
phosphatidylinositol 3-kinase-Akt/
protein kinase B and p44/42 MAPK, and the inhibition of the
mitochondrial permeability transition pore (MPTP). Recently published data indicate that the JAK/STAT signaling pathway, which mediates the metabolic actions of
leptin, also plays a pivotal role in cardioprotection. Consequently, in the present study 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 (10 nM), administered at reperfusion, in the presence or absence of the JAK2 inhibitor,
AG-490 (5 μM).
Leptin reduced
infarct size significantly (control, 60.05 ± 7.41% vs.
leptin treated, 29.9 ± 3.24%, P < 0.05), protection being abolished by
AG-490. Time course studies revealed that
leptin caused a 171% (P < 0.001) increase in STAT3/
tyrosine-705 phosphorylation at 2.5 min reperfusion; however, increases were not seen at 5, 10, 15, or 30 min reperfusion. Contrasting with STAT3, Akt/
serine-473 phosphorylation was not significantly increased until 15 min into the reperfusion phase (140%, P < 0.05).
AG-490 blocked the
leptin-induced rise in STAT3 phosphorylation seen at 2.5 min reperfusion but did not influence Akt/
serine-473 phosphorylation at 15 min.
Leptin reduced the
MPTP opening (P < 0.001), which was blocked by
AG-490. This is the first study to yield evidence that JAK/STAT signaling linked to the
MPTP plays a role in
leptin-induced cardioprotection. Under the experimental conditions employed, STAT3 phosphorylation appears to have occurred earlier during reperfusion than that of Akt. Further research into the interactions between these two signaling pathways in the setting of I/R injury is, however, required.