Leptin-induced cardioprotection involves JAK/STAT signaling that may be linked to the mitochondrial permeability transition pore
- 1 October 2010
- journal article
- research article
- Published by American Physiological Society in American Journal of Physiology-Heart and Circulatory Physiology
- Vol. 299 (4), H1265-H1270
- https://doi.org/10.1152/ajpheart.00092.2010
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.This publication has 34 references indexed in Scilit:
- The Cardioprotective Actions of Leptin Are Lost in the Zucker Obese (fa/fa) RatJournal of Cardiovascular Pharmacology, 2009
- Function of Mitochondrial Stat3 in Cellular RespirationScience, 2009
- The myocardial JAK/STAT pathway: From protection to failurePharmacology & Therapeutics, 2008
- Regulating RISK: a role for JAK-STAT signaling in postconditioning?American Journal of Physiology-Heart and Circulatory Physiology, 2008
- Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusionBasic Research in Cardiology, 2008
- Dual activation of STAT-3 and Akt is required during the trigger phase of ischaemic preconditioningCardiovascular Research, 2008
- Cardioprotection by Ischemic Postconditioning Is Lost in Aged and STAT3-Deficient MiceCirculation Research, 2008
- Urocortin prevents mitochondrial permeability transition in response to reperfusion injury indirectly by reducing oxidative stressAmerican Journal of Physiology-Heart and Circulatory Physiology, 2007
- Role of the JAK–STAT pathway in myocardial injuryTrends in Molecular Medicine, 2007
- Leptin, the obesity‐associated hormone, exhibits direct cardioprotective effectsBritish Journal of Pharmacology, 2006