We recently reported that the heart expresses functional receptors for the anorexigenicglucagon-like peptide (GLP)-2. Activation of these cardiac receptors affected basal heartperformance through extracellular regulated kinase (ERK1/2) activation. Since ERK1/2 is considered one of the prosurvival kinases of postconditioning cardioprotective pathways, wehypothesized 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 and120-min reperfusion (I/R group). In GLP-2 group, hearts received 20-min GLP-2 (10-7 M)infusion at the beginning of the 120-min reperfusion. Perfusion pressure and left ventricularpressure (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 infarctsize 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, theERK1/2 inhibitor, PD98059, or the mitochondrial KATP channel blocker, 5-Hydroxydecanoate. GLP-2 effects were accompanied by increased phosphorylations of protein kinase B (PKB/Akt), ERK1/2 and glycogen synthase kinase (GSK3β). After 7-minreperfusion, Wortmannin blocked Akt and GSK3β phosphorylation. After 30-minreperfusion, Wortmannin inhibited phosphorylation of all kinases. In conclusion, 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.
Postconditioning with Glucagon Like Peptide-2 Reduces Ischemia/Reperfusion Injury in Isolated Rat Hearts: Role of Survival Kinases and Mitochondrial KATP Channels
PASQUA, Teresa;CERRA, Maria Carmela;ANGELONE, Tommaso
2012-01-01
Abstract
We recently reported that the heart expresses functional receptors for the anorexigenicglucagon-like peptide (GLP)-2. Activation of these cardiac receptors affected basal heartperformance through extracellular regulated kinase (ERK1/2) activation. Since ERK1/2 is considered one of the prosurvival kinases of postconditioning cardioprotective pathways, wehypothesized 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 and120-min reperfusion (I/R group). In GLP-2 group, hearts received 20-min GLP-2 (10-7 M)infusion at the beginning of the 120-min reperfusion. Perfusion pressure and left ventricularpressure (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 infarctsize 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, theERK1/2 inhibitor, PD98059, or the mitochondrial KATP channel blocker, 5-Hydroxydecanoate. GLP-2 effects were accompanied by increased phosphorylations of protein kinase B (PKB/Akt), ERK1/2 and glycogen synthase kinase (GSK3β). After 7-minreperfusion, Wortmannin blocked Akt and GSK3β phosphorylation. After 30-minreperfusion, Wortmannin inhibited phosphorylation of all kinases. In conclusion, 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
