Role of protein kinase system in the signal transduction of stretch-mediated protooncogene expression and hypertrophy of cardiac myocytes

Abstract

To examine the molecular mechanisms by which mechanical stimuli induce protooncogene expression and hypertrophy of cardiac myocytes directly, we cultured rat neonatal cardiac myocytes in deformable dishes and imposed mechanical load on adherent cultured cardiac myocytes by stretching the dishes. Myocyte stretching increased total cell RNA content and mRNA levels of c-fos and skeletal α-actin followed by the aminoacid incorporation into cardiac proteins. CAT assay analysis indicated that the sequences containing serum response element were required for the efficient transcription of c-fos gene by stretching. This accumulation of c-fos mRNA by myocyte stretching was inhibited markedly by down-regulation of protein kinase C. Moreover, myocyte stretching increased inositol phosphate levels. These findings suggests that mechanical stimuli might directly induce protooncogene expression possibly via protein kinase C activation. Furthermore, we observed the activation of MAP kinase by myocytes stretching. This result suggests that MAP kinase activation induced by mechanical stimuli might increase the efficiency of protein synthesis on ribosomes induced by mechanical stimuli.