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 × DNp38α MAPK mice, but not bigenic β1-AR × 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 × DNp38α MAPK mice, but not bigenic β2-AR × 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.
Pallavi S. Peter, Jennifer E. Brady, Lin Yan, Wei Chen, Stefan Engelhardt, Yibin Wang, Junichi Sadoshima, Stephen F. Vatner, Dorothy E. Vatner
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