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

• Published in: Physiological reports Vol. 13; no. 15; pp. e70488 - n/a
• Main Authors: Aubry, Adrien, Kebbe, Mariana, Al‐Katat, Aya, Villeneuve, Louis, Calderone, Angelino
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2025; John Wiley and Sons Inc; Wiley
• Subjects: Adrenergic receptors; Animals; Animals, Newborn; Antibodies; Cardiomyocytes; Cell cycle; Cell Cycle - drug effects; cell cycle re‐entry; Cells, Cultured; Down-regulation; Fibroblasts; Heart; Heart Ventricles - cytology; Heart Ventricles - drug effects; Heart Ventricles - metabolism; Imidazoles - pharmacology; Isoproterenol - pharmacology; Kinases; Laboratories; MAP kinase; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; neonatal rat ventricular cardiomyocytes; Neonates; Nestin; Nestin - genetics; Nestin - metabolism; Norepinephrine; Norepinephrine - pharmacology; Original; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; p38α/β MAPK; Phosphorylation; PKC isoforms; Protein kinase C; Proteins; Pyridines; Rats; Rats, Sprague-Dawley; Regular Manuscript; Rodents; Selenium; siRNA; Ventricle; β1/2‐adrenergic receptors; mM; p38α/β MAPK; neonatal rat ventricular cardiomyocytes; cell cycle re‐entry; nestin; β1/2‐adrenergic receptors; PKC isoforms
• ISSN: 2051-817X; 2051-817X
• DOI: 10.14814/phy2.70488

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.