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1 Hypertension and Vascular Research Division.Department of Medicine, Henry Ford Hospital, Detroit, Michigan, USA
* To whom correspondence should be addressed. E-mail: mclapointe{at}aol.com;mlapoin1@hfhs.org.
Upon induction of cyclooxygenase-2 (COX-2), neonatal ventricular myocytes (VM) synthesize mainly prostaglandin E2 (PGE2). The biological effects of PGE2 are mediated through four different G-protein-coupled receptor (GPCR) subtypes (EP1-4). We have previously shown that PGE2 stimulates cAMP production and induces hypertrophy of VM. Since the EP4 receptor is coupled to adenylate cyclase and increases in cAMP, we hypothesized that PGE2 induces hypertrophic growth of cardiac myocytes through a signaling cascade involving EP4/cAMP and activation of protein kinase A (PKA). To test this, we used primary cultures of VM and measured 3H-leucine incorporation into total protein. An EP4 antagonist was able to partially block PGE2 induction of protein synthesis and prevented PGE2-dependent increases in cell surface area and activity of the atrial natriuretic factor promoter, two other indicators of hypertrophic growth. Surprisingly, a PKA inhibitor had no effect. In other cell types, G-proteincoupled receptor activation has been shown to transactivate the epidermal growth factor receptor (EGFR), resulting in p42/44 mitogen-activated protein kinase (MAPK) activation and cell growth. Immunoprecipitation of myocyte lysates demonstrated that the EGFR was rapidly phosphorylated by PGE2 in VM and the EP4 antagonist blocked this. In addition, a selective EGFR inhibitor, AG1478, completely blocked PGE2-induced protein synthesis. We also found that PGE2 rapidly phosphorylated p42/44 MAPK, which was inhibited by the EP4 antagonist and by AG1478. Finally, the p42/44 MAPK inhibitor PD98053 (PD, 25 µmol/L) blocked PGE2- induced protein synthesis. Altogether, we believe these are the first data suggesting that PGE2 induce protein synthesis in cardiac myocytes in part via activation of the EP4receptor and subsequent activation of p42/44MAPK. Activation of p42/44 MAPK is independent of the common cAMP/PKA pathway and involves EP4-dependent transactivation of EGFR.
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