In neonatal rat ventricular myocytes, NRG-1 induced cardiomyocyte hypertrophy via multiple nonredundant pathways, with maximal effects on [(3)H]phenylalanine uptake and F-actin polymerization at 20 ng/ml.
NRG-ErbB signaling triggers multiple nonredundant pathways (PI-3-kinase, p70S6K, and MEK-MAPK-RSK) to induce hypertrophy in postnatal ventricular myocytes.
Neuregulins are a family of growth-promoting peptides known to be important in neural and mesenchymal tissue development. Targeted disruption of neuregulin (NRG)-1 or one of two of its cognate receptors, ErbB2 or ErbB4, results in embryonic lethality because of failure of the heart to develop. Although expression of NRGs and their receptors declines after midembryogenesis, both ErbB2 and ErbB4 are present in cardiac myocytes, and NRG-1 expression remains inducible in primary cultures of coronary microvascular endothelial cells from adult rat ventricular muscle. In neonatal rat ventricular myocytes, a soluble NRG-1, recombinant human glial growth factor-2, increased (3)Hphenylalanine uptake and induced expression of atrial natriuretic factor (ANF) and sarcomeric F-actin polymerization. The effect of NRG-1 on (3)Hphenylalanine uptake and sarcomeric F-actin polymerization was maximal at 20 ng/ml but declined at higher concentrations. NRG-1 activated p42/p44 mitogen-activated protein kinase (MAPK) extracellular signal-regulated kinase (ERK)-2/ERK1 and ribosomal S6 kinase (RSK)-2 (90-kDa ribosomal S6 kinase), both of which could be inhibited by the MAPK/ERK kinase-1 antagonist PD-098059. NRG-1 also activated 70-kDa ribosomal S6 kinase, which was inhibited by either rapamycin or wortmannin. Activation of these pathways exhibited the same "biphasic" response to increasing NRG-1 concentrations. Wortmannin and LY-294002 blocked sarcomeric F-actin polymerization but not (3)Hphenylalanine uptake or ANF expression, whereas PD-098059 consistently blocked both (3)Hphenylalanine uptake and ANF expression but not actin polymerization. In contrast, rapamycin inhibited (3)Hphenylalanine uptake and F-actin polymerization but not ANF expression. Thus NRG-ErbB signaling triggers multiple nonredundant pathways in postnatal ventricular myocytes.
Baliga et al. (Mon,) conducted a other in Cardiomyocyte hypertrophy. Neuregulin-1 (NRG-1) was evaluated on [(3)H]phenylalanine uptake, ANF expression, and sarcomeric F-actin polymerization. In neonatal rat ventricular myocytes, NRG-1 induced cardiomyocyte hypertrophy via multiple nonredundant pathways, with maximal effects on [(3)H]phenylalanine uptake and F-actin polymerization at 20 ng/ml.