The role of PKCε-dependent signaling for cardiac differentiation

Protein kinase Cepsilon (PKCe) exerts a wellknown cardio-protective activity in ischemia–reperfusion injury and plays a pivotal role in stem cell proliferation and differentiation. Although many studies have been performed on physiological and morphological effects of PKCe mis-expression in cardiomyocytes, molecular information on the role of PKCe on early cardiac gene expression are still lacking. We addressed the molecular role of PKCe in cardiac cells using mouse cardiomyocytes and rat bone marrow mesenchymal stem cells. We show that PKCe is modulated in cardiac differentiation producing an opposite regulation of the cardiac genes NK2 transcription factor related, locus 5 (nkx2.5) and GATA binding protein 4 (gata4) both in vivo and in vitro. Phospho-extracellular regulated mitogen-activated protein kinase 1/2 (p-ERK1/2) levels increase in PKCe over-expressing cells, while pkce siRNAs produce a decrease in p-ERK1/2. Indeed, pharmacological inhibition of ERK1/2 rescues the expression levels of both nkx2.5 and gata4, suggesting that a reinforced (mitogen-activated protein kinase) MAPK signaling is at the basis of the observed inhibition of cardiac gene expression in the PKCe over-expressing hearts. We demonstrate that PKCe is critical for cardiac cell early gene expression evidencing that this protein is a regulator that has to be fine tuned in precursor cardiac cells.