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 indu ce cardiac hypertrophy via activation of members of the phospholipase C (PL C) family. The expression pattern of the PLC beta isozyme subfamily was inv estigated in neonatal rat cardiomyocytes after stimulation with different h ypertrophic stimuli, Under control conditions and after stimulation with no repinephrine, cardiomyocytes expressed similar amounts of PLC beta 3 mRNA. In the presence of fetal calf serum (FCS), additional expression of PLC bet a 1 was induced. Growth hormone (GH) and insulin-like growth factor-1 (IGF- I) both induced a substantial increase in PLC beta 3 mRNA expression. The r esponse to GH could not be abolished by the ICE-I receptor blocker ICE-I an alogue indicating an ICE-I-independent action of GH, The upregulation of PL C beta 3 by ICE-I was abolished by preincubation of cardiomyocytes with the ICE-I receptor antagonist IGF-I analogue, the tyrosine kinase inhibitor ge nistein, 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 ICE-I was abolished by preincubation with antisense oli gos against PLC beta 3, It is concluded that the expression of PLC beta iso zymes in cardiomyocytes is differentially regulated by different hypertroph ic stimuli. The upregulation of PLC beta 3 by ICE-I is dependent on the act ivity of tyrosine kinase, ERR, PI3 kinase, and p70 S6 kinase and PLC beta 3 expression seems to be required for the induction of immediate early genes by IGF-I. The involvement of the PLC beta subfamily in signal transduction of receptors other than G-protein-coupled receptors is suggested. (C) 2000 Academic Press.