Role of phosphatidylinositol 3-kinase activation in the hypertrophic growth of adult ventricular cardiomyocytes

Abstract

Objective: The present study investigated whether activation of phosphatidylinositol 3-kinase (PI3-kinase) is involved in the stimulation of hypertrophic growth of adult ventricular cardiomyocytes under α- or β-adrenoceptor stimulation. Methods: Adult ventricular rat cardiomyocytes were used either directly after isolation (day 1 culture) or after cultivation for 6 days in presence of 20% fetal calf serum (day 7 culture). PI3-kinase activity was determined in extracts of cardiomyocytes after immunoprecipitation with an antibody against the p85 subunit of PI3-kinase. The influence of PI3-kinase inhibition on myocardial growth was determined using the specific PI3-kinase inhibitors wortmannin and LY294002. Results: In day 1 cultures α-adrenoceptor stimulation, but not β-adrenoceptor stimulation caused activation of PI3-kinase. In response to α-adrenoceptor stimulation but not β-adrenoceptor stimulation an acceleration of protein synthesis (incorporation of ¹⁴C-phenylalanine) and an increase in the total masses of cellular protein and RNA was observed. In these cultures inhibition of PI3-kinase attenuated the acceleration of protein synthesis and the increase in cellular masses of protein or RNA in response to α-adrenoceptor stimulation. In day 7 cultures α- and β-adrenoceptor stimulation caused activation of PI3-kinase and increased protein synthesis. In these cultures inhibition of PI3-kinase attenuated the growth response to α- and β-adrenoceptor stimulation. Conclusions: PI3-kinase activation via protein kinase C-dependent or cAMP-dependent pathways is required for hypertrophic growth of adult cardiomyocytes.

Hypertrophy, Myocytes, Protein kinases, Second messengers, Signal transduction