TYROSINE KINASE AND C-JUN NH2-TERMINAL KINASE MEDIATE HYPERTROPHIC RESPONSES TO PROSTAGLANDIN-F2-ALPHA IN CULTURED NEONATAL RAT VENTRICULARMYOCYTES

Myocardial infarction results in focal areas of ischemia, hypoxia, nec rosis, and decreased contractile function. To compensate for loss of c ontractile function, remaining viable myocytes undergo hypertrophic gr owth. Prostaglandin F-2 alpha (PGF(2 alpha)), which is released from c ells of the myocardium during periods of stress such as hypoxia or isc hemia/reperfusion, has recently been shown to stimulate hypertrophic g rowth in neonatal rat ventricular myocytes. In the present study, we d etermine which growth-related intracellular pathways are required for PGF(2 alpha) to induce morphological and genetic features characterist ic of the hypertrophic phenotype. In cardiomyocytes, PGF(2 alpha) incr eases the hydrolysis of inositol phosphates and induces the translocat ion of protein kinase C epsilon to the myocyte membrane, consistent wi th PGF(2 alpha) receptor coupling to G(q). PGF(2 alpha) also activates the extracellular signal-regulated kinase (ERK) and p38 mitogen-activ ated protein kinase pathways. Surprisingly, studies using pharmacologi cal inhibitors and transfection of dominant-interfering proteins demon strate that PGF(2 alpha)-induced myocyte hypertrophy occurs independen t of either PKC, p38, or ERK pathways. Additional studies demonstrate that PGF(2 alpha) stimulates protein tyrosine phosphorylation and acti vates c-Jun NH2-terminal kinase and suggest that these pathways mediat e hypertrophic growth in response to PGF(2 alpha).