The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo.
Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.
Bueno
O F
OF
Department of Pediatrics, University of Cincinnati, Children's Hospital Medical Center, Division of Molecular Cardiovascular Biology, Cincinnati, Ohio, USA.
De Windt
L J
LJ
Lim
H W
HW
Tymitz
K M
KM
Witt
S A
SA
Kimball
T R
TR
Molkentin
J D
JD
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics; D002395:Catecholamines / Q000494:pharmacology; D002478:Cells, Cultured; D004274:DNA, Recombinant; D019332:Endothelin-1 / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D010656:Phenylephrine / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats
D002395:Catecholamines; D004274:DNA, Recombinant; D019332:Endothelin-1; D012333:RNA, Messenger; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D017027:Protein Tyrosine Phosphatases