Impairment of cardioprotective PI3K-Aktsignaling by post-infarct ventricularremodeling is compensated by anERK-mediated pathway |
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Authors: | T. Miki T. Miura M. Tanno M. Nishihara K. Naitoh T. Sato A. Takahashi K. Shimamoto |
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Affiliation: | (1) Second Dept. of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo 060-8543, Japan;(2) Dept. of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan |
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Abstract: | Recently we found that post-infarct remodeling disrupts PI3KAkt signaling triggered by erythropoietin (EPO) but an unknown compensatory mechanism preserves EPO-induced protection against infarction in those hearts. In this study, we examined the possibility that ERK-mediated signaling is the compensatory mechanism affording protection in post-infarct remodeled hearts. Four weeks after coronary ligation in situ (post-MI group, post-MI) or a sham operation (sham group, Sham), hearts were isolated, perfused and subjected to 25-min global ischemia/2-h reperfusion. Infarct size was expressed as a percentage of risk area size (%I/R), from which scarred infarct by coronary ligation was excluded. EPO infusion (5 U/ml) before ischemia reduced %I/R similarly in Sham and post-MI (from 62.0 ± 5.1 to 39.4 ± 4.8 in Sham and from 58.6 ± 6.6 to 36.3 ± 3.8 in post-MI). PD98059, a MEK1/2 inhibitor, abolished this EPO-induced protection in post-MI (%I/R = 60.7 ± 4.9) but not in Sham (%I/R = 35.1 ± 5.4). EPO induced PI3Kdependent phosphorylation of Akt in Sham but not in post-MI. EPO increased phosphorylation levels of ERK1/2 both in Sham and post-MI, but this phosphorylation was diminished by a PI3K inhibitor in Sham but not in post-MI. These results suggest that PI3K-independent activation of ERK compensates the lack of signal input from the PI3K-Akt pathway to achieve EPO-induced protection in the remodeled myocardium. |
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Keywords: | erythropoietin PI3K-Akt ERK remodeled hearts infarct size |
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