F006 Critical role of ERK1/2 in erythropoietin-mediated cardioprotection compared with ischemic postconditioning - 17/04/09
Résumé |
Background |
Erythropoietin (EPO) and ischemic postconditioning (IPost) have been shown to attenuate myocardial reperfusion injury. Aims: This study compared the mechanisms of the acute cardioprotective effect of EPO and IPost and tested whether they share similar signalling pathways in isolated rat hearts, focussing on phosphatidylinositol 3-kinase (PI3K)/Akt and ERK1/2 pathways.
Methods |
Hearts were subjected to 25 min global ischemia followed by 30 min of reperfusion. 7 groups were tested: control (no intervention); IPost (3 cycles of 10 sec reperfusion/10 sec ischemia at the onset of reperfusion); EPO (1000 UI/kg, at the onset of reperfusion); IPost+PI3K inhibitor wortmannin (Wort, 1 μmol/L); EPO+Wort; IPost+ERK1/2 inhibitor PD98059 (PD, 10 μmol/L); EPO+PD.
Results |
IPost- or EPO-treated hearts exhibited significantly improved left ventricular function reflected by an increase in postischemic recovery of left ventricular developed pressure (LVDP) and improved contractility (dP/dtmax) and relaxation (dP/dtmin) indexes throughout the reperfusion period compared with control hearts. EPO showed better LVDP than IPost at 30min reperfusion (73.18±10.23 mmHg vs. 48.11±7.92 mmHg, ρ<0.05). Wort or PD fully prevented both EPO and IPost-mediated cardioprotection. Phosphorylation of myocardial Akt was significantly increased in both IPost and EPO groups. However, phosphorylation levels of ERK1/2 and the downstream target GSK-3β were significantly increased in EPO group only.
Conclusion |
EPO and IPost share similar intracellular cardioprotective pathways. EPO exhibits better cardioprotective effects than IPost against reperfusion injury leading to great hopes in EPO as a pharmacological agent of postconditioning. This increased resistance to myocardial ischemia induced by EPO seems to be mediated by an enhanced phosphorylation of ERK1/2.
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