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

## TL;DR

Norepinephrine prevents heart cells from re-entering the cell cycle, especially in a specific group of cells that do not express nestin.

## Contribution

The study reveals a novel mechanism by which sympathetic signals inhibit cell cycle re-entry in neonatal cardiomyocytes via p38α/β MAPK.

## Key findings

- Norepinephrine and isoproterenol reduce cell cycle re-entry in neonatal cardiomyocytes.
- SB203580 restores cell cycle re-entry in the nestin-negative subpopulation.
- PKC-α downregulation suppresses nestin expression and cell cycle re-entry.

## Abstract

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 β1/2‐adrenergic receptor selectively inhibited the cell cycle re‐entry of the nestin(−)‐NNVM subpopulation via recruitment of p38α/β MAPK.