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Received for publication September 19, 2005.
Revised December 21, 2005.
Accepted for publication December 22, 2005.
Post-infarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin (EPO) receptor is modified by post-infarct remodeling. Four weeks after induction of myocardial infarction by coronary ligation in post-MI group (post-MI) or a sham operation in sham group (Sham), rat hearts were isolated and subjected to 25-min global ischemia/2-hr reperfusion. Infarct size was expressed as a percent of risk area (i.e., left ventricle) from which scarred infarct was excluded (%I/R). The heart weight was 15% larger in post-MI, but there was no inter-group difference in plasma EPO levels or myocardial EPO receptor levels. EPO infusion (5 U/ml) significantly reduced %I/R from 59.9±4.1 to 36.2±4.2 in Sham and from 58.1±5.0 to 35.2±4.0 in post-MI. This EPO-induced protection was sensitive to a PI3K inhibitor, LY-294002, in Sham. However, neither LY-294002 nor wortmannin inhibited the EPO-induced protection in post-MI. Phosphorylation of Jak2 by EPO was attenuated and phosphorylation of Akt was not detected in post-MI. A guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one, and a mitoKATP channel blocker, 5-hydroxydecanoate, inhibited EPO-induced protection in both Sham and post-MI. Suppressor of cytokine signaling (SOCS)-1 protein level was higher by 50% in post-MI than in Sham, though SOCS-3 levels were similar. These findings suggest that post-infarct remodeling disrupts cellular signaling from the EPO receptor to PI3K presumably by increased SOCS-1. However, in the remodeled myocardium, lack of PI3K/Akt activation by the EPO receptor appears to be compensated by a mechanism upstream of the guanylyl cyclase/mitoKATP channel pathway to achieve EPO-induced protection.
Key words:
ATP sensitive potassium channel, Akt, erythropoietin, guanylyl cyclase, infarct size, ventricular remodeling
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