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 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 weeks 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 Myh7 and Nppa expression and also shifted Glut1/Glut4 toward their fetal profile. Transcriptomic analysis identified two novel NRG1-regulated genes: NRG1 reversed TAC-induced upregulation of the skeletal muscle gene Mybpc2 and induced the expression of Popdc2. Furthermore, NRG1 increased expression of Gja1 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.