Systems analysis reveals neuregulin-1 control of cardiomyocyte size and shape mediated by distinct PI3K and p38 pathways

Cardiac hypertrophy is a common precursor to heart failure, but its cellular manifestations—changes in cardiomyocyte size and shape—are regulated by poorly understood signaling networks. Here, we combined high-content morphological profiling, proteomics, and systems modeling to characterize the diverse forms of hypertrophy induced by angiotensin II, endothelin-1, insulin growth factor-1, and neuregulin-1 (Nrg1). Reverse-phase protein array profiling and partial least squares regression modeling revealed that AKT, GSK3, and MAPK signaling are differentially regulated by hypertrophic agonists and are predictive of distinct phenotypic outcomes. Nrg1 uniquely induced cardiomyocyte elongation in both neonatal rat and human iPSC-derived cardiomyocytes, in addition to increasing cell area. Pharmacological perturbations demonstrated that Nrg1-induced elongation and area expansion both require PI3K activity, whereas p38 selectively mediates cell area. A logic-based network model incorporating dual-specificity phosphatases were sufficient to capture the amplifying PI3K and transient p38 signaling dynamics driving phenotypic changes. Together, these results identify distinct signaling cascades by which Nrg1 coordinates cardiomyocyte size and shape, providing mechanistic insight into how hypertrophic remodeling can be differentially regulated. This systems approach provides new insight into the pathways that drive distinct forms of cardiomyocyte hypertrophy, highlighting opportunities to selectively target maladaptive remodeling in heart failure.