Inhibition of p38 alpha MAPK rescues cardiomyopathy induced by overexpressed beta 2-adrenergic receptor, but not beta 1-adrenergic receptor.
We examined the role of p38alpha MAPK in mediating cardiomyopathy in mice overexpressing beta(1)-adrenergic receptor (beta(1)-AR) or beta(2)-AR by mating them with dominant-negative p38alpha (DNp38alpha) MAPK mice. Both beta(1)-AR and beta(2)-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 p38alpha MAPK by mating beta(1)-AR Tg and beta(2)-AR Tg mice with DNp38alpha MAPK mice, which rescued the depressed LVEF and reduced apoptosis and fibrosis in bigenic beta(2)-AR x DNp38alpha MAPK mice, but not bigenic beta(1)-AR x DNp38alpha MAPK mice, and failed to reduce myocyte hypertrophy in either group. G(salpha) was increased in both beta(1)-AR Tg and beta(2)-AR Tg mice and was still present in bigenic beta(1)-AR x DNp38alpha MAPK mice, but not bigenic beta(2)-AR x DNp38alpha MAPK mice. This suggests that p38alpha MAPK is one critical downstream signal for the development of cardiomyopathy following chronic beta(2)-AR stimulation, but other kinases may be more important in ameliorating the adverse effects of chronic beta(1)-AR stimulation.
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- Receptors, Adrenergic, beta-2
- Receptors, Adrenergic, beta-1
- Mitogen-Activated Protein Kinase 14
- Mice, Transgenic
- Mice
- MAP Kinase Signaling System
- Immunology
- Cardiomyopathies
- Animals
- 42 Health sciences
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Receptors, Adrenergic, beta-2
- Receptors, Adrenergic, beta-1
- Mitogen-Activated Protein Kinase 14
- Mice, Transgenic
- Mice
- MAP Kinase Signaling System
- Immunology
- Cardiomyopathies
- Animals
- 42 Health sciences