Neuregulin-1β augments adaptive concentric remodeling and systolic function without exacerbating hypertrophy during pressure overload

Neuregulin-1β (NRG1) improves cardiac output in heart failure patients, yet concerns remain that erythroblastic oncogene B (ErbB) activation may promote maladaptive hypertrophy, particularly during hemodynamic stress. We investigated how NRG1 influences structural, functional, and molecular remodeling during pressure overload. Male and female C57BL/6NRj mice underwent transverse aortic constriction (TAC) or sham surgery and received saline or recombinant NRG1 via osmotic minipumps or daily injection. In male mice, NRG1 increased ejection fraction at 1 and 4 wk after TAC. NRG1 accentuated TAC-induced concentric remodeling without increasing left ventricular weight or cardiomyocyte cross-sectional area. It markedly reduced fibrosis and macrophage infiltration and prevented progression toward early cardiac decompensation. NRG1 amplified TAC-induced <i>Myh7</i> and <i>Nppa</i> expression and also shifted <i>Glut1/Glut4</i> toward their fetal profile. Transcriptomic analysis identified two novel NRG1-regulated genes: NRG1 reversed TAC-induced upregulation of the skeletal muscle gene myosin binding protein C (<i>Mybpc2</i>) and induced the expression of Popeye domain-containing protein 2 (<i>Popdc2</i>). Furthermore, NRG1 increased expression of <i>Gja1</i> and localization of connexin 43 at the intercalated disc, consistent with enhanced electrical coupling. In female mice, NRG1 increased systolic function and regulated similar molecular targets yet did not reduce the modest increase in fibrosis that was observed. In conclusion, our findings show that NRG1 promotes adaptive molecular and structural remodeling under pressure overload and enhances contractile performance without exacerbating hypertrophy. The identification of NRG1-responsive genes linked to contraction and conduction highlights potential mechanisms and supports further exploration of NRG1-based strategies for cardiac disease.<b>NEW & NOTEWORTHY</b> Our study demonstrates that neuregulin-1β (NRG1) enhances systolic function during pressure overload while promoting adaptive remodeling without exacerbating hypertrophy. NRG1 regulates fetal gene programs in both sexes and reduces fibrosis in male mice. The identification of myosin binding protein C (<i>Mybpc2</i>) and Popeye domain-containing protein 2 (<i>Popdc2</i>) as novel NRG1-responsive genes reveals previously unrecognized mechanisms underlying its cardioprotective effects. These findings support further investigation of NRG1-based therapeutic strategies and highlight potential sex-specific responses.