title: Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore.
abstract: 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.
authors.affiliation: The Hatter Cardiovascular Institute, University College London and Hospital Medical School, London, United Kingdom.
authors.forename: Christopher C T
authors.initials: CC
authors.lastname: Smith
authors.forename: Richard A
authors.initials: RA
authors.lastname: Dixon
authors.forename: Abigail M
authors.initials: AM
authors.lastname: Wynne
authors.forename: Louise
authors.initials: L
authors.lastname: Theodorou
authors.forename: Sang-Ging
authors.initials: SG
authors.lastname: Ong
authors.forename: Sapna
authors.initials: S
authors.lastname: Subrayan
authors.forename: Sean M
authors.initials: SM
authors.lastname: Davidson
authors.forename: Derek J
authors.initials: DJ
authors.lastname: Hausenloy
authors.forename: Derek M
authors.initials: DM
authors.lastname: Yellon
mesh_terms: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D053614:Janus Kinase 2 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020738:Leptin / Q000627:therapeutic use*; D008297:Male; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D050791:STAT Transcription Factors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D020738:Leptin; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D053612:Janus Kinases