Norepinephrine inhibits cell cycle re-entry of neonatal rat ventricular cardiomyocytes characterized by the absence of de novo nestin expression.

The p38α/β MAPK inhibitor SB203580 in the presence of a phorbol ester (protein kinase C activator) induced cell cycle re-entry of two subpopulations of neonatal rat ventricular cardiomyocytes (NNVMs) distinguished by the absence or de novo nestin expression. Recent studies have reported that the β-adrenergic receptor inhibited the cell cycle re-entry of ventricular cardiomyocytes. The present study tested the hypothesis that sympathetic recruitment of p38α/β MAPK signaling suppressed cell cycle re-entry of one or both subpopulations of 1-day-old NNVMs. Norepinephrine (NE; 1 μM) or Isoproterenol (ISO; 1 μM) treatment of NNVMs for 24 h significantly attenuated 5-bromo-2'-deoxyuridine incorporation, and NE increased p38α MAPK phosphorylation. SB203580 (10 μM) treatment of NE/ISO-stimulated NNVMs selectively re-established the cell cycle re-entry of the subpopulation distinguished by the absence of de novo nestin expression. Phorbol 12,13-dibutyrate (PDBu; 100 nM) treatment attenuated 5-bromo-2'-deoxyuridine incorporation, and SB203580 treatment predominantly initiated re-entry into the cell cycle of the NNVM subpopulation characterized by de novo nestin expression. siRNA-mediated PKC-α protein downregulation in NNVMs selectively suppressed PDBu/SB203580-mediated de novo nestin and subsequent cell cycle re-entry. Thus, sympathetic stimuli acting via the β_1/2-adrenergic receptor selectively inhibited the cell cycle re-entry of the nestin^(-)-NNVM subpopulation via recruitment of p38α/β MAPK.