Inhibition of p38α MAPK rescues cardiomyopathy induced by overexpressed β2-adrenergic receptor, but not β1-adrenergic receptor
Year: 2007
Type: article
Abstract: 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.
DOI: 10.1172/jci29576
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
Awards: G152786771, TRANSMURAL SR REGULATION IN LV HYPERTROPHY, Age and Gender Differences in Apoptosis and Stem Cells, G2072582855, G241436969, Aging Effects on Cardiovascular Function, Integrative Mechanisms in Cardiovascular Disease, CARDIOVASCULAR CONTROL IN NORMAL AND DISEASE STATES, Regulation of myocardial growth and death by GSK-3, G3410819162, BETA-ADRENERGIC SIGNALING, DENERVATION AND HEART FAILURE, G4048960512, Catalytic activation of adenylyl cyclase type V, G429204276, G4320055159, G444970711, Redox regulation in myocardial disease, G4533333338, G538767246, Myocardial Hypertrophy and Heart Failure, Cardiovascular Control in Normal and Disease States, Mechanisms of myocardial ischemia and reperfusion, G7639128960, G965472155
OpenAlex ID: W2003305266