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

Abstract

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. Gsα 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.