Alteration in erythropoietin-induced cardioprotective signaling by postinfarct ventricular remodeling

Postinfarct remodeling impairs mechanisms of ischemic preconditioning. We examined whether myocardial response to activation of the erythropoietin ( EPO) receptor is modified by postinfarct remodeling. Four weeks after induction of myocardial infarction ( MI) 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- h reperfusion. Infarct size was expressed as a percentage 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 intergroup 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 phosphatidylinositol 3- kinase ( PI3K) inhibitor, 2-( 4- morpholinyl)- 8- phenyl- 4H- 1- benzopyran- 4- one LY294002), in sham. However, neither LY294002 nor wortmannin inhibited the EPO- induced protection in post- MI. Phosphorylation of Janus kinase 2 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 mitochondrial ATP- sensitive K (+) channel ( mitoK ATP 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, although SOCS- 3 levels were similar. These findings suggest that postinfarct 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 seems to be compensated by a mechanism upstream of the guanylyl cyclase-mitoK(ATP) channel pathway to achieve EPO- induced protection.