Tyrosine kinase and c-Jun NH2-terminal kinase mediate hypertrophic responses to prostaglandin F(2α) in cultured neonatal rat ventricular myocytes

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 NH2-terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF(2α).