(Circulation. 2001;103:1453.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Cardiac Overexpression of a Gq Inhibitor Blocks Induction of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Activity in In Vivo Pressure Overload
From the Department of Medicine and Cell Biology (G.E., S.V.N.P., A.R., L.M., H.A.R.) and the Department of Surgery (W.J.K.), Duke University Medical Center, Durham, NC.
Correspondence to Howard A. Rockman, MD, Department of Medicine and Cell Biology, Duke University Medical Center, DUMC 3104, Durham, NC, 27710. E-mail h.rockman{at}duke.edu
Background—Understanding the cellular signals that initiate cardiac hypertrophy is of critical importance in identifying the pathways that mediate heart failure. The family of mitogen-activated protein kinases (MAPKs), including the extracellular signal–regulated kinases (ERKs), c-Jun NH2-terminal kinase (JNK), and p38 MAPKs, may play specific roles in myocardial growth and function.
Methods and Results—To
determine the mechanism of activation of MAPK pathways during the
development of cardiac hypertrophy, we evaluated the induction of MAPK
activity after aortic constriction in wild-type and in 2 types of
cardiac gene-targeted mice: one overexpressing a carboxyl-terminal
peptide of G
q that inhibits
Gq-mediated signaling (TG GqI mouse) and another
overexpressing a carboxyl-terminal peptide of ß-adrenergic receptor
kinase-1 that inhibits Gß
signaling (TG ßARKct mouse). Wild-type
mice with pressure overload showed an acute induction of JNK, followed
by the induction of p38/p38ß at 3 days and ERK at 7 days. Both JNK
and p38 activity remained elevated at 7 days after banding. In TG GqI
mice, hypertrophy was significantly attenuated, and induction of ERK
and JNK activity was abolished, whereas the induction of p38 and p38ß
was robust, but delayed. By contrast, all 3 MAPK pathways were
activated by aortic constriction in the TG ßARKct hearts, suggesting
a role for Gq, but not
Gß.
Conclusions—Taken together, these data show that the induction of ERK and JNK activity in in vivo pressure-overload hypertrophy is mediated through the stimulation of Gq-coupled receptors and that non–Gq-mediated pathways are recruited to activate p38 and p38ß.
Key Words: receptors • kinases • genes • hypertrophy
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