Copyright © 2005, European Society of Cardiology
PKC 
-induced activation of MAPK pathway is required for bFGF-stimulated proliferation of coronary smooth muscle cells
Leibniz-Institute for Arteriosclerosis Research, University of Münster, Domagkstr. 3, 48149 Münster, Germany and Department of Cardiology and Angiology, University of Münster, Albert-Schweitzer Str. 33, 48129 Münster, Germany
* Corresponding author. Tel.: +49 251 83 55326; fax: +49 251 83 52980. Email address: skaletz{at}uni-muenster.de
Objective: Basic fibroblast growth factor (bFGF)-stimulated proliferation of coronary smooth muscle cells (cSMC) contributes to the pathogenesis of arteriosclerosis and restenosis. However, the molecular mechanisms involved are not fully understood. We have shown previously that protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) are required for the bFGF-stimulated mitogenic process in bovine cSMC. In this study, we determined the PKC isoform(s) involved and investigated their functional role in the bFGF-stimulated signaling and cell cycle progression in human and bovine cSMC.
Methods and Results: Downregulation of PKC by phorbol 12-myristate 13-acetate (PMA) inhibited bFGF-induced DNA synthesis, the activation of MAPK, and the expression of c-myc, demonstrating the involvement of PMA-sensitive PKC isoforms in growth factor-induced proliferation and the MAPK pathway. The PMA-sensitive classical PKC isoforms 
, β, 
and novel PKC isoforms 
and 
were found in human cSMC. Whereas blocking of the classical PKC isoforms had no influence, the suppression of PKC by genetic and pharmacological approaches inhibited the bFGF-stimulated c-Raf1–MEK–MAPK–c-myc signaling and DNA synthesis in cSMC. In contrast to PKC , our results showed that bFGF activated PKC by phosphorylation in a time-dependent manner. In addition, inhibition of PKC induced a hypophosphorylation of the retinoblastoma protein and suppression of the cyclins D1 and A, demonstrating the importance of PKC for bFGF-induced cell cycle progression through the G1 phase in cSMC.
Conclusions: Our results show that PKC is required for the bFGF-stimulated c-Raf1–MEK–MAPK–c-myc signaling pathway involved in the proliferation of cSMC. Therefore, it may be an interesting therapeutic target for preventing proliferative vascular disorders.
KEYWORDS Growth factors; MAP kinase; Signal transduction; Smooth muscle cells; Protein kinase C
1 Present address: Department of Cardiology, Heart and Diabetes Center Bad Oeynhausen, Germany.
Time for primary review 18 days
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