Trophic effects of the cyclooxygenase-2 product prostaglandin E2 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 niRNA 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 [H-3]leucine incorporation, comparable to the known hypertrophic factor phenylephrine (1.6-fold). Because PGE(2) exerts different effects through 4 receptor subtypes (EP1, EP2, EP3, and EP4), we investigated whether these receptors are functional in myocytes. Treatment of NVMs with the selective EP1/EP3 agonist sulprostone significantly increased protein synthesis (1.7-fold), whereas the EP1/EP2 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.