Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 117, Issue 5, Pages 1335-1343Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI29576
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Funding
- NHLBI NIH HHS [P01 HL069020, HL 69020, HL 69752, R01 HL065182, P01 HL059139, R01 HL033107, T32 HL069752, HL 65183, HL 67724, R01 HL067724, HL 59139, HL 33107, HL 65182, R37 HL033107] Funding Source: Medline
- NIA NIH HHS [AG 14121, R01 AG023137, R01 AG014121, AG 23039, AG 23137, R01 AG023039] Funding Source: Medline
- NIGMS NIH HHS [R01 GM067773, GM 67773] Funding Source: Medline
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We examined the role of p38 alpha MAPK in mediating cardiomyopathy in mice overexpressing beta(1)-adrenergic receptor (beta(1)-AR) or beta(2)-AR by mating them with dominant-negative p38 alpha (DNp38 alpha) 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 p38 alpha MAPK by mating beta(1)-AR Tg and beta(2)-AR Tg mice with DNp38 alpha MAPK mice, which rescued the depressed LVEF and reduced apoptosis and fibrosis in bigenic beta(2)-AR x DNp38 alpha MAPK mice, but not bigenic beta(1)-AR x DNp38 alpha MAPK mice, and failed to reduce myocyte hypertrophy in either group. G(s alpha) was increased in both beta(1)-AR Tg and beta(2)-AR Tg mice and was still present in bigenic beta(1)-AR x DNp38 alpha MAPK mice, but not bigenic beta(2)-AR x DNp38 alpha MAPK mice. This suggests that p38 alpha 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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