Role of 14-3-3-mediated p38 mitogen-activated protein kinase inhibition in cardiac myocyte survival.
14-3-3 family members are dimeric phosphoserine-binding proteins that regulate signal transduction, apoptotic, and checkpoint control pathways. Targeted expression of dominant-negative 14-3-3eta (DN-14-3-3) to murine postnatal cardiac tissue potentiates Ask1, c-jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) activation. DN-14-3-3 mice are unable to compensate for pressure overload, which results in increased mortality, dilated cardiomyopathy, and cardiac myocyte apoptosis. To evaluate the relative role of p38 MAPK activity in the DN-14-3-3 phenotype, we inhibited cardiac p38 MAPK activity by pharmacological and genetic methods. Intraperitoneal injection of SB202190, an inhibitor of p38alpha and p38beta MAPK activity, markedly increased the ability of DN-14-3-3 mice to compensate for pressure overload, with decreased mortality. DN-14-3-3 mice were bred with transgenic mice in which dominant-negative p38alpha (DN-p38alpha) or dominant-negative p38beta (DN-p38beta) MAPK expression was targeted to the heart. Compound transgenic DN-14-3-3/DN-p38beta mice, and to a lesser extent compound transgenic DN-14-3-3/DN-p38alpha mice, exhibited reduced mortality and cardiac myocyte apoptosis in response to pressure overload, demonstrating that DN-14-3-3 promotes cardiac apoptosis due to stimulation of p38 MAPK activity.
Center for Cardiovascular Research, Department of Medicine, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110, USA.
Shaosong
S
Zhang
Jie
J
Ren
Cindy E
CE
Zhang
Ilya
I
Treskov
Yibin
Y
Wang
Anthony J
AJ
Muslin
D048948:14-3-3 Proteins; D000818:Animals; D001011:Aorta / Q000502:physiology; D017209:Apoptosis / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000517:prevention & control; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003251:Constriction, Pathologic; D003433:Crosses, Genetic; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018390:Gene Targeting; D005799:Genes, Dominant; D007093:Imidazoles / Q000494:pharmacology; D007274:Injections, Intraperitoneal; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015996:Survival Rate; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases
D048948:14-3-3 Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014446:Tyrosine 3-Monooxygenase; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole