Stimulation of the four isoforms of receptor tyrosine kinase ErbB4, but not ErbB1, confers cardiomyocyte hypertrophy

Epidermal growth factor (EGF) receptors (ErbB1-ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF-like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1-mediated hypertrophy occurred despite robust activation of extracellular-regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1-induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM-a/JM-b and CYT-1/CYT-2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1-induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown-resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect.