Role and Relation of p70 S6 and Extracellular Signal-Regulated Kinases in the Phenotypic Changes of Hypertrophy of Cardiac Myocytes

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Cardiac hypertrophy is characterized by increased cardiomyocyte protein synthesis, increased cell volume, and a shift in cardiac-specific gene expression to fetal isoforms. Using neonatal rat cardiomyocytes stimulated with fetal calf serum (FCS) as a model for cardiac hypertrophy, the present study investigated the role of 2 signal transduction pathways, extracellular signal-regulated kinase (ERK) and p70 S6 kinase (p70S6K), in the attendant phenotype changes. FCS evoked both ERK and p70S6K activity, peaking at 20-40 min, and simultancously increased cardiac myocyte protein synthesis (evaluated by [^3H]leucine incorporation and total cellular protein content), cell size (evaluated by morphometry and fluorescence-activated cell sorter analysis) and expression of a fetal isoform of the muscle specific gene skeletal α-actin (SKA). Rapamycin, a specific inhibitor of the mammalian target of rapamycin (mTOR), which is an upstream signaling of p70S6K, completely inhibited FCS-induced cell size increases and protein synthesis, but had no effect on SKA mRNA expression. PD98059, which inhibited ERK activity, attenuated cardiac-specific gene expression in a dose-depcndent manner, but had no influence on protein synthesis or cell size. These results indicate divergent roles for the ERK and p70S6K path-ways in the phenotypic changes associated with cardiac hypertrophy.
社団法人日本循環器学会の論文
2000-08-20