Trophic effects of the cyclooxygenase-2 product prostaglandin E(2) in cardiac myocytes.
Interleukin-1beta (IL-1beta), a proinflammatory cytokine, induces cyclooxygenase-2 (COX-2) in cultured neonatal ventricular myocytes (NVMs), resulting in the preferential production of prostaglandin E(2) (PGE(2)). To explain the preferential PGE(2) release by myocytes, we studied whether its specific synthase, PGE(2) synthase (PGES), is also induced by IL-1beta. Because COX-2 has been extensively associated with cell growth, we questioned whether PGE(2) plays a role in cardiac cell growth. IL-1beta--treated myocytes showed induction of PGES protein and mRNA by Western blot and reverse transcription--polymerase chain reaction, respectively. Immunofluorescence studies revealed perinuclear localization of COX-2 and PGES in IL-1beta--treated myocytes. Exogenous PGE(2) increased protein synthesis in NVMs, as indicated by a 1.6-fold increase in [(3)H]leucine incorporation, comparable to the known hypertrophic factor phenylephrine (1.6-fold). Because PGE(2) exerts different effects through 4 receptor subtypes (EP(1), EP(2), EP(3), and EP(4)), we investigated whether these receptors are functional in myocytes. Treatment of NVMs with the selective EP(1)/EP(3) agonist sulprostone significantly increased protein synthesis (1.7-fold), whereas the EP(1)/EP(2) antagonist AH6809 blocked this effect by 43%. In contrast, AH6809 had no effect on PGE(2)-induced protein synthesis. Regarding second messengers, sulprostone had no effect on cAMP, whereas PGE(2) increased it. We concluded that (1) PGE(2) production requires the induction of its specific synthase; (2) in myocytes, the inducible enzymes COX-2 and PGES are perinuclear; and (3) PGE(2) and sulprostone induce cardiac myocyte growth but seem to activate a different subset of EP receptors.
Mendez
Mariela
M
Hypertension and Vascular Research Division, Henry Ford Hospital, Detroit, MI 48202-2689, USA.
LaPointe
Margot C
MC
D000818:Animals; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D007375:Interleukin-1 / Q000494:pharmacology; D007527:Isoenzymes / Q000096:biosynthesis* / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D058306:Receptors, Prostaglandin E, EP1 Subtype; D013347:Subcellular Fractions
D007375:Interleukin-1; D007527:Isoenzymes; D018078:Receptors, Prostaglandin E; D058306:Receptors, Prostaglandin E, EP1 Subtype; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone