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Postconditioning with glucagon like peptide-2 reduces ischemia/reperfusion injury in isolated rat hearts: role of survival kinases and mitochondrial KATP channels

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Abstract

We recently reported that heart expresses functional receptors for the anorexigenic glucagon-like peptide (GLP)-2. Activation of these cardiac receptors affected basal heart performance through extracellular regulated kinase (ERK1/2) activation. Since ERK1/2 is considered one of the prosurvival kinases of postconditioning cardioprotective pathways, we hypothesized that GLP-2 directly protects the heart against ischemia/reperfusion (I/R) injury via prosurvival kinases. Wistar rat hearts were retrogradely perfused on a Langendorff perfusion apparatus. After 40-min stabilization, hearts underwent 30-min global ischemia and 120-min reperfusion (I/R group). In GLP-2 group, the hearts received 20-min GLP-2 (10−7 M) infusion at the beginning of the 120-min reperfusion. Perfusion pressure and left ventricular pressure (LVP) were monitored. Infarct size was evaluated by nitroblue-tetrazolium staining. Compared with the I/R group, GLP-2-treated hearts showed a significant reduction of infarct size and of postischemic diastolic LVP (index of contracture), together with a sharp improvement of developed LVP recovery (index of contractility). The protective effects were abolished by co-infusion with phosphatidylinositol 3-kinase inhibitor, Wortmannin (WT), the ERK1/2 inhibitor, PD98059, or the mitochondrial KATP channel blocker, 5-hydroxydecanoate. GLP-2 effects were accompanied by increased phosphorylation of protein kinase B (PKB/Akt), ERK1/2 and glycogen synthase kinase (GSK3β). After 7-min reperfusion, WT blocked Akt and GSK3β phosphorylation. After 30-min reperfusion, WT inhibited phosphorylation of all kinases. In conclusion, the data suggest that GLP-2, given in early reperfusion, as postconditioning, protects against myocardial I/R injury, limiting infarct size, and improving post-ischemic mechanical recovery. It seems that the GLP-2-protection of rat heart involves multiple prosurvival kinases and mitochondrial KATP channels.

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Acknowledgments

This work was supported by the Ministero dell’Istruzione, dell’Università e della Ricerca of Italy (Programma di Ricerca Scientifica di Interesse Nazionale: M. C. Cerra; MURST 60 %: M. C. Cerra, P. Pagliaro, C. Penna, T. Angelone), the “Dottorato di Ricerca in Biologia Animale”, the “Dottorato di Fisiologia” University of Turin, the “Istituto Nazionale di Ricerca Cardiovascolare” (M. C. Cerra, T. Angelone, T. Pasqua), Regione Piemonte and “Compagnia San Paolo”- Italy (P. Pagliaro, C. Penna). The authors would like to thank Dr C. Angotti and Dr F. Tullio for the technical assistance.

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Authors and Affiliations

  1. Department of Clinical and Biological Sciences, University of Turin, Region Gonzole 10, 10043, Orbassano, TO, Italy

    Claudia Penna, Maria-Giulia Perrelli & Pasquale Pagliaro

  2. Department of Cell Biology, University of Calabria, Arcavacata di Rende, CS, Italy

    Teresa Pasqua, Maria Carmela Cerra & Tommaso Angelone

  3. Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, CS, Italy

    Maria Carmela Cerra

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  1. Claudia Penna
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  2. Teresa Pasqua
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Correspondence to Pasquale Pagliaro.

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Penna, C., Pasqua, T., Perrelli, MG. et al. Postconditioning with glucagon like peptide-2 reduces ischemia/reperfusion injury in isolated rat hearts: role of survival kinases and mitochondrial KATP channels. Basic Res Cardiol 107, 272 (2012). https://doi.org/10.1007/s00395-012-0272-6

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