© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Tamoxifen and ICI 182,780 negatively influenced cardiac cell growth via an estrogen receptor-independent mechanism
aDepartment of Physiology, University of Montreal, Montreal, Quebec, Canada
bMontreal Heart Institute, Research Center, 5000 Belanger Street East, Montreal, Quebec, Canada H1T 1C8
cDepartment of Biochemistry, University of Montreal, Montreal, Quebec, Canada
calderon{at}icm.umontreal.ca
* Corresponding author. Tel.: +1-514-376-3330x3710; fax: +1-514-376-1355.
Background: Recent studies have demonstrated that selective estrogen receptor modulators (SERMs) reduced identifiable risk factors implicated in cardiovascular disease. Despite this observation, the direct effect of SERMs on cardiac cell growth remains unexplored. Methods: Neonatal rat cardiac myocytes (CM) and fibroblasts (CF) were exposed to either the partial estrogen receptor agonist/antagonist 4-OH tamoxifen (e.g., SERM) or the pure estrogen receptor antagonist ICI 182,780 and the effect on DNA synthesis, cell cycle protein expression and extracellular signal-regulated kinase (ERK1/2) phosphorylation were assessed. Results: The treatment of CM and CF with either 4-OH tamoxifen or ICI 182,780 decreased DNA synthesis in the absence of apoptosis via an estrogen receptor-independent pathway. In CM and CF, 4-OH tamoxifen and ICI 182,780 treatment reduced proliferating cell nuclear antigen protein expression and concomitantly increased p27Kip1. 4-OH Tamoxifen and ICI 182,780 treatment increased ERK1/2 phosphorylation in CM and CF, and ERK1/2 kinase (MEK)-dependent inhibition of ERK1/2 activation attenuated ICI 182,780-mediated suppression of DNA synthesis. Conclusion: These data are the first to describe cardiac cells as novel targets of SERMs and ICI 182,780, and highlight the role of the ERK1/2 pathway in the suppression of DNA synthesis.
KEYWORDS Cell culture/isolation; Signal transduction; Protein kinases; Receptors; Remodeling
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