Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway.
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 PI3K-dependent 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.
Miki
Takayuki
T
Second Department of Internal Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
Miura
Tetsuji
T
Tanno
Masaya
M
Nishihara
Masahiro
M
Naitoh
Kazuyuki
K
Sato
Takahiro
T
Takahashi
Akari
A
Shimamoto
Kazuaki
K
D000818:Animals; D004921:Erythropoietin / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020257:Ventricular Remodeling / Q000502:physiology*
D004921:Erythropoietin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases