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Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway

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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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Authors and Affiliations

  1. Second Dept. of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan

    T. Miki, T. Miura, M. Tanno, M. Nishihara, K. Naitoh, T. Sato, A. Takahashi & K. Shimamoto

  2. Dept. of Pharmacology, Sapporo Medical University School of Medicine, Sapporo, Japan

    M. Tanno

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  1. T. Miki
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  2. T. Miura
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  3. M. Tanno
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  4. M. Nishihara
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  5. K. Naitoh
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  6. T. Sato
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  7. A. Takahashi
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  8. K. Shimamoto
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Correspondence to T. Miura.

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Miki, T., Miura, T., Tanno, M. et al. Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. Basic Res Cardiol 102, 163–170 (2007). https://doi.org/10.1007/s00395-006-0622-3

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  • DOI: https://doi.org/10.1007/s00395-006-0622-3

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