NRG-1-induced cardiomyocyte hypertrophy. Role of PI-3-kinase, p70(S6K), and MEK-MAPK-RSK

Neuregulins are a family of growth-promoting peptides known to be important in neural and mesenchymal tissue development. Targeted disruption of neure gulin (NRG)-1 or one of two of its cognate receptors, ErbB2 or ErbB4, resul ts in embryonic lethality because of failure of the heart to develop. Altho ugh 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 endothelia l cells from adult rat ventricular muscle. In neonatal rat ventricular myoc ytes, a soluble NRG-1, recombinant human glial growth factor-2, increased [ H-3]phenylalanine uptake and induced expression of atrial natriuretic facto r (ANF) and sarcomeric F-actin polymerization. The effect of NRG-1 on [H-3] phenylalanine uptake and sarcomeric F-actin polymerization was maximal at 2 0 ng/ml but declined at higher concentrations. NRG-1 activated p42/p44 mito gen-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 inhibite d by either rapamycin or wortmannin. Activation of these pathways exhibited the same "biphasic" response to increasing NRG-1 concentrations. Wortmanni n and LY-294002 blocked sarcomeric F-actin polymerization but not [H-3]phen ylalanine uptake or ANF expression, whereas PD-098059 consistently blocked both [H-3]phenylalanine uptake and ANF expression but not actin polymerizat ion. In contrast, rapamycin inhibited [H-3]phenylalanine uptake and F-actin polymerization but not ANF expression. Thus NRG-ErbB signaling triggers mu ltiple nonredundant pathways in postnatal ventricular myocytes.