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.
Peter
Pallavi S
PS
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, 185 South Orange Avenue, Newark, NJ 07103, USA.
Brady
Jennifer E
JE
Yan
Lin
L
Chen
Wei
W
Engelhardt
Stefan
S
Wang
Yibin
Y
Sadoshima
Junichi
J
Vatner
Stephen F
SF
Vatner
Dorothy E
DE
D000818:Animals; D009202:Cardiomyopathies / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000502:physiology; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics / Q000502:physiology*; D018343:Receptors, Adrenergic, beta-2 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D048308:Mitogen-Activated Protein Kinase 14