CaM kinase signaling induces cardiac hypertrophy and activates the MEF2 transcription factor in vivo.
Hypertrophic growth is an adaptive response of the heart to diverse pathological stimuli and is characterized by cardiomyocyte enlargement, sarcomere assembly, and activation of a fetal program of cardiac gene expression. A variety of Ca(2+)-dependent signal transduction pathways have been implicated in cardiac hypertrophy, but whether these pathways are independent or interdependent and whether there is specificity among them are unclear. Previously, we showed that activation of the Ca(2+)/calmodulin-dependent protein phosphatase calcineurin or its target transcription factor NFAT3 was sufficient to evoke myocardial hypertrophy in vivo. Here, we show that activated Ca(2+)/calmodulin-dependent protein kinases-I and -IV (CaMKI and CaMKIV) also induce hypertrophic responses in cardiomyocytes in vitro and that CaMKIV overexpressing mice develop cardiac hypertrophy with increased left ventricular end-diastolic diameter and decreased fractional shortening. Crossing this transgenic line with mice expressing a constitutively activated form of NFAT3 revealed synergy between these signaling pathways. We further show that CaMKIV activates the transcription factor MEF2 through a posttranslational mechanism in the hypertrophic heart in vivo. Activated calcineurin is a less efficient activator of MEF2-dependent transcription, suggesting that the calcineurin/NFAT and CaMK/MEF2 pathways act in parallel. These findings identify MEF2 as a downstream target for CaMK signaling in the hypertrophic heart and suggest that the CaMK and calcineurin pathways preferentially target different transcription factors to induce cardiac hypertrophy.
Passier
R
R
Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75235-9148, USA.
Zeng
H
H
Frey
N
N
Naya
F J
FJ
Nicol
R L
RL
McKinsey
T A
TA
Overbeek
P
P
Richardson
J A
JA
Grant
S R
SR
Olson
E N
EN
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics; D019703:Calcineurin / Q000378:metabolism; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D006801:Humans; D008156:Luciferases / Q000235:genetics; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D018995:Myosin Heavy Chains / Q000235:genetics; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*
D004268:DNA-Binding Proteins; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D014157:Transcription Factors; D009320:Atrial Natriuretic Factor; D008156:Luciferases; C517683:CAMK4 protein, human; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C517685:Camk4 protein, mouse; C517686:Camk4 protein, rat; D019703:Calcineurin; D018995:Myosin Heavy Chains