Tyrosine Kinase and c-Jun NH₂-Terminal Kinase Mediate Hypertrophic Responses to Prostaglandin F₂ in Cultured Neonatal Rat Ventricular Myocytes

From the Department of Pharmacology (J.W.A., V.P.S., J.H.B.), University of California, San Diego, La Jolla, Calif, and the Department of Physiological Science (S.A.H.), University of California, Los Angeles.

Correspondence to Joan Heller Brown, PhD, Department of Pharmacology, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0636. E-mail jhbrown{at}ucsd.edu

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 F₂ (PGF₂), 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 PGF₂ to induce morphological and genetic features characteristic of the hypertrophic phenotype. In cardiomyocytes, PGF₂ increases the hydrolysis of inositol phosphates and induces the translocation of protein kinase C to the myocyte membrane, consistent with PGF₂ receptor coupling to G_q. PGF₂ 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 PGF₂-induced myocyte hypertrophy occurs independent of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF₂ stimulates protein tyrosine phosphorylation and activates c-Jun NH₂-terminal kinase and suggest that these pathways mediate hypertrophic growth in response to PGF₂.

Key Words: prostaglandin • cardiac hypertrophy • extracellular signal-regulated kinase • c-Jun NH₂-terminal kinase • tyrosine kinase

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