Tyrosine Kinase and c-Jun NH 2 -Terminal Kinase Mediate Hypertrophic Responses to Prostaglandin F 2α in Cultured Neonatal Rat Ventricular Myocytes

Abstract

Abstract —Myocardial infarction results in focal areas of ischemia, hypoxia, necrosis, and decreased contractile function. To compensate for loss of contractile function, remaining viable myocytes undergo hypertrophic growth. Prostaglandin F 2α (PGF 2α ), which is released from cells of the myocardium during periods of stress such as hypoxia or ischemia/reperfusion, has recently been shown to stimulate hypertrophic growth in neonatal rat ventricular myocytes. In the present study, we determine which growth-related intracellular pathways are required for PGF 2α to induce morphological and genetic features characteristic of the hypertrophic phenotype. In cardiomyocytes, PGF 2α increases the hydrolysis of inositol phosphates and induces the translocation of protein kinase Cε to the myocyte membrane, consistent with PGF 2α receptor coupling to G q . PGF 2α also activates the extracellular signal–regulated kinase (ERK) and p38 mitogen-activated protein kinase pathways. Surprisingly, studies using pharmacological inhibitors and transfection of dominant-interfering proteins demonstrate that PGF 2α -induced myocyte hypertrophy occurs independent of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF 2α stimulates protein tyrosine phosphorylation and activates c-Jun NH 2 -terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF 2α .