Phorbol ester stimulates cyclooxygenase-2 expression and prostanoid production in cardiac myocytes.
Phorbol-12-myristate- 13-acetate (PMA) has been shown to induce hypertrophy of cardiac myocytes. The prostaglandin endoperoxide H synthase isoform 2 (cyclooxygenase-2, COX-2) has been associated with enhanced growth and/or proliferation of several types of cells. Thus we studied whether PMA induces COX-2 and prostanoid products PGE(2) and PGF(2alpha) in neonatal ventricular myocytes and whether endogenous COX-2 products participate in their growth. In addition, we examined whether PMA affects interleukin-1beta (IL-1beta) stimulation of COX-2 and PGE(2) production. PMA (0.1 micromol/l) stimulated growth, as indicated by a 1.6-fold increase in [(3)H]leucine incorporation. PMA increased COX-2 protein levels 2. 8-fold, PGE(2) 3.7-fold, and PGF(2alpha) 2.9-fold. Inhibition of either p38 kinase or protein kinase C (PKC) prevented PMA-stimulated COX-2. Inhibition of COX-2 with either indomethacin or NS-398 had no effect on PMA-stimulated [(3)H]leucine incorporation. Exogenous administration of PGF(2alpha), but not PGE(2), stimulated protein synthesis. Treatment with IL-1beta (5 ng/ml) increased COX-2 protein levels 42-fold, whereas cotreatment with IL-1beta and PMA stimulated COX-2 protein only 32-fold. IL-1beta did not affect control or PMA-stimulated protein synthesis. These findings indicate that: 1) PMA, acting through PKC and p38 kinase, enhances COX-2 expression, but chronic treatment with PMA partially inhibits IL-1beta stimulation of COX-2; and 2) exogenous PGF(2alpha) is involved in neonatal ventricular myocyte growth but endogenous COX-2 products are not.
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, Michigan 48202, USA.
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Schuette
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LaPointe
D000818:Animals; D000831:Animals, Newborn; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015237:Dinoprost / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D009578:Nitrobenzenes / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007375:Interleukin-1; D007527:Isoenzymes; D009578:Nitrobenzenes; D011453:Prostaglandins; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D015237:Dinoprost; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D007930:Leucine; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D007213:Indomethacin