© 1998 by European Society of Cardiology
Copyright © 1998, European Society of Cardiology
Stimulation of P2Y receptors activates c-fos gene expression and inhibits DNA synthesis in cultured cardiac fibroblasts
aLaboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institute of Health, Baltimore, MD 21224, USA
bMolecular Neurobiology Unit, Division of Basic Medical Sciences, Royal Free Hospital School of Medicine, Rowland Hill Street, Hampstead, London, NW3 2PF, UK
* Corresponding author. Present address: The University of Michigan, Kinesiology; Dept. of Movement Science, 401 Washtenaw Avenue, Ann Arbor, MI 48109-2214. Tel. (+1-313) 647 7645; Fax (+1-313) 936 1925; E-mail: boluytm@umich.edu
Objectives: The aims of this study were to determine (1) whether neonatal rat cardiac fibroblasts (CAFB) express P2Y receptors; (2) whether CAFB respond to extracellular ATP by inducing expression of c-fos mRNA; and (3) whether extracellular ATP modulates norepinephrine (NE)-stimulated cell growth in CAFB. Methods: Expression of P2Y1 and P2Y2 receptors and induction of c-fos were examined by Northern blot analysis. CAFB growth was assessed by measuring [3H]thymidine incorporation and DNA content. P2Y receptor pharmacology was studied using various ATP analogues. Results: Northern blot analysis of polyA enriched RNA confirmed that at least 2 subtypes of P2Y receptors (P2Y1 and P2Y2) are expressed in cultured CAFB. Extracellular ATP induced the expression of c-fos mRNA through a pathway that was sensitive to inhibitors of protein kinase C (PKC), but not to inhibitors of intracellular Ca2+ signaling. Extracellular ATP inhibited the NE-stimulated increases in DNA content and in [3H]thymidine incorporation into DNA. Whereas the potency order for stimulation of c-fos expression was ATP = UTP > ADP > adenosine, the potency order to inhibit the NE-induced increase of [3H]thymidine incorporation into DNA was ATP > ADP > UTP > adenosine. Conclusions: These data demonstrate that CAFB express both P2Y1 and P2Y2 receptor mRNA and that CAFB respond to P2Y receptor stimulation by induction of c-fos and inhibition of DNA synthesis. These findings suggest that the effects of ATP on [3H]thymidine incorporation into DNA and on expression of c-fos mRNA are exerted via distinct P2Y receptor subtypes.
KEYWORDS P2Y receptor; Rat cardiac fibroblast; Cell proliferation; c-fos
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