In contrast, Rac1cKI mice expressing palmitoylation-resistant Rac1C178S solely in cardiomyocytes develop more severe cardiac disease in response to pharmacological and genetic models of hypertrophic stress, including AngII infusion, pressure overload, and cardiomyocyte-specific overexpression of AT1R that is associated with enhanced myocardial phosphorylation of PKA targets in all cases, indicating unexpected adaptive roles for signaling by S-palmitoylated Rac1 in restraining cardiac hypertrophy, maladaptation, and hyperactivation of the PKA-dependent phosphoproteome in response to stress. Here, AGT is linked to cardiac hypertrophy.