Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β₂-adrenergic receptor, but not β₁-adrenergic receptor

We examined the role of p38α MAPK in mediating cardiomyopathy in mice overexpressing β₁-adrenergic receptor (β₁-AR) or β₂-AR by mating them with dominant-negative p38α (DNp38α) MAPK mice. Both β₁-AR and β₂-AR Tg mice had enhanced LV ejection fraction (LVEF) as young adults and developed similar cardiomyopathy at 11-15 months, characterized by reduced LVEF, myocyte hypertrophy, fibrosis, and apoptosis. We inhibited p38α MAPK by mating β₁-AR Tg and β₂-AR Tg mice with DNp38α MAPK mice, which rescued the depressed LVEF and reduced apoptosis and fibrosis in bigenic β₂-AR x DNp38α MAPK mice, but not bigenic β₁-AR x DNp38α MAPK mice, and failed to reduce myocyte hypertrophy in either group. G_sα was increased in both β₁-AR Tg and β₂-AR Tg mice and was still present in bigenic β₁-AR x DNp38α MAPK mice, but not bigenic β₂-AR x DNp38α MAPK mice. This suggests that p38α MAPK is one critical downstream signal for the development of cardiomyopathy following chronic β₂-AR stimulation, but other kinases may be more important in ameliorating the adverse effects of chronic β₁-AR stimulation.