Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptor
Pallavi S. Peter, Jennifer E. Brady, Lin Yan, Wei Chen, Stefan Engelhardt, Yibin Wang, Junichi Sadoshima, Stephen F. Vatner, Dorothy E. Vatner
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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Research Article Cardiology

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 × 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.

Authors

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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Figure 2

Histological examples of the necrosis and fibrosis in old WT (A–C), old β2-AR Tg (D–F), and old bigenic β2-AR Tg × DNp38α MAPK mice (G–I) are shown in H&E stains (A, D, and G; original magnification, ×4).

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Histological examples of the necrosis and fibrosis in old WT (A–C), old ...
Picric acid sirius red staining (B, E, and H; original magnification, ×10) was used to quantitate collagen. Myocyte cross-sectional area was visualized using wheat germ agglutinin staining (C, F, and I; original magnification, ×40). The enlarged myocytes for both β2-AR Tg and bigenic β2-AR Tg × DNp38α MAPK mice. Note that there were marked increases in fibrosis and necrosis in β2-AR Tg mice, which were ameliorated substantially in bigenic β2-AR Tg × DNp38α MAPK mice.