Differential regulation of phospholipase C-beta isozymes in cardiomyocyte hypertrophy

Cardiac hypertrophy is a major predictor of heart failure and of morbidity and mortality in developed countries. Many hormones and growth factors induce cardiac hypertrophy via activation of members of the phospholipase C (PLC) family. The expression pattern of the PLCbeta isozyme subfamily was investigated in neonatal rat cardiomyocytes after stimulation with different hypertrophic stimuli. Under control conditions and after stimulation with norepinephrine, cardiomyocytes expressed similar amounts of PLCbeta3 mRNA. In the presence of fetal calf serum (FCS), additional expression of PLCbeta1 was induced. Growth hormone (GH) and insulin-like growth factor-I (IGF-I) both induced a substantial increase in PLCbeta3 mRNA expression. The response to GH could not be abolished by the IGF-I receptor blocker IGF-I analogue indicating an IGF-I-independent action of GH. The upregulation of PLCbeta3 by IGF-I was abolished by preincubation of cardiomyocytes with the IGF-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor genistein, the extracellular signal-related kinase (ERK) inhibitor PD 98059, the phosphatidylinositol-3- (PI-3) kinase inhibitor wortmannin and the p70 S6 kinase inhibitor rapamycin. Induction of the immediate early genes c-myc, c-fos, and c-jun by IGF-I was abolished by preincubation with antisense oligos against PLCbeta3. It is concluded that the expression of PLCbeta isozymes in cardiomyocytes is differentially regulated by different hypertrophic stimuli. The upregulation of PLCbeta3 by IGF-I is dependent on the activity of tyrosine kinase, ERK, PI3 kinase, and p70 S6 kinase and PLCbeta3 expression seems to be required for the induction of immediate early genes by IGF-I. The involvement of the PLCbeta subfamily in signal transduction of receptors other than G-protein-coupled receptors is suggested.