BACKGROUND AND PURPOSE: Protection against ischaemia-reperfusion (I/R) injury involves PI3K-Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K-Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity. EXPERIMENTAL APPROACH: The influence of leptin on I/R injury was examined in perfused hearts from C57Bl/6 J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell-signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes. KEY RESULTS: Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non-phosphorylated STAT3, and of total AMP-activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture. CONCLUSIONS AND IMPLICATIONS: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3-Akt and p44/42 MAPK pathways.
BACKGROUND AND PURPOSE: Protection against ischaemia-reperfusion (I/R) injury involves PI3K-Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K-Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity. EXPERIMENTAL APPROACH: The influence of leptin on I/R injury was examined in perfused hearts from C57Bl/6 J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell-signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes. KEY RESULTS:Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non-phosphorylated STAT3, and of total AMP-activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture. CONCLUSIONS AND IMPLICATIONS: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3-Akt and p44/42 MAPK pathways.
Authors: John Wityak; Frank W Hobbs; Daniel S Gardner; Joseph B Santella; Joseph J Petraitis; Jung-Hui Sun; Margaret F Favata; Andrea J Daulerio; Kurumi Y Horiuchi; Robert A Copeland; Peggy A Scherle; Bruce D Jaffe; James M Trzaskos; Ronald L Magolda; George L Trainor; John V Duncia Journal: Bioorg Med Chem Lett Date: 2004-03-22 Impact factor: 2.823
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Authors: Enrica Golia; Giuseppe Limongelli; Francesco Natale; Fabio Fimiani; Valeria Maddaloni; Pina Elvira Russo; Lucia Riegler; Renatomaria Bianchi; Mario Crisci; Gaetano Di Palma; Paolo Golino; Maria Giovanna Russo; Raffaele Calabrò; Paolo Calabrò Journal: World J Cardiol Date: 2014-07-26
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Authors: Shiang Y Lim; Sean M Davidson; Ajeev J Paramanathan; Christopher C T Smith; Derek M Yellon; Derek J Hausenloy Journal: J Cell Mol Med Date: 2008-04-08 Impact factor: 5.310