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Cardiovascular Research 2003 60(2):438-446; doi:10.1016/j.cardiores.2003.08.007
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

Prostacyclin production in rat aortic smooth muscle cells: role of protein kinase C, phospholipase D and cyclooxygenase-2 expression

Miguel A Frias, Frédérique Dubouloz, Michela C Rebsamen and Ursula Lang*

Division of Endocrinology and Diabetology, University Hospital, 24 rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland

*Corresponding author. Tel.: +41-22-372-93-18; fax: +41-22-372-93-29. Email address: ursula.lang{at}medecine.unige.ch

Objective: The present study was designed to investigate the role of protein kinase C (PKC) and phospholipase D (PLD) in angiotensin II (AngII)- and phorbol ester (PMA)-induced cyclooxygenase-2 (COX-2) expression and prostacyclin (PGI2) production in rat aortic smooth muscle cells (VSMC). Methods: Prostacyclin production in cultured VSMC was determined by radioimmunoassay. PKC activity was examined by measuring the transfer of 32P from ({gamma}-32P)ATP to histone III-S. COX-2 expression was determined by Western blotting. To measure PLD activity, thin layer chromatography was used. Results: AngII (50 nM) and PMA (100 nM) promoted the translocation of PKC activity from the cytosol to the membranes within 30 min, followed by a strong increase in PLD activity as well as COX-2 expression and PGI2 production. After 48 h exposure to PMA, PKC was downregulated resulting in a complete suppression of its activity. PKC-downregulation and the PKC inhibitor CGP41251 abolished PMA- and AngII-induced PLD activation, suppressed the stimulatory effect of PMA on COX-2 expression and PGI2 production and strongly inhibited that of AngII. Furthermore, AngII- and PMA-induced PGI2 production depended on protein synthesis and COX-2 but not COX-1 activity. Inhibition of PLD-mediated phosphatidic acid (PA) formation by 1% 1-butanol abolished AngII-induced COX-2 expression and PGI2 secretion, while dioctanoyl PA increased COX-2 expression and PGI2 production in a time- and concentration-dependent manner. Conclusion: Our results indicate that in VSMC, AngII promotes PGI2 production to a large extent through a rise in COX-2 expression which is mediated by PA generated from increased PKC-dependent PLD activity.

KEYWORDS Cell culture/isolation; Hormones; Signal transduction; Prostaglandins

Time for primary review 35 days


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