The major novel finding of this study is that diabetes is associated with a reduction in EGFR/erbB2 heterodimer signaling in the heart and that activation of EGFR/erbB2 signaling via EGF leads to markedly improved cardiac recovery from I/R by opposing diabetes and/or ischemia induced changes in ERK1/2, p38 MAP kinase, AKT and FOXO signaling. This evidence concerns the gene MAPK3 and ischemia.