A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.
In response to numerous pathologic stimuli, the myocardium undergoes a hypertrophic response characterized by increased myocardial cell size and activation of fetal cardiac genes. We show that cardiac hypertrophy is induced by the calcium-dependent phosphatase calcineurin, which dephosphorylates the transcription factor NF-AT3, enabling it to translocate to the nucleus. NF-AT3 interacts with the cardiac zinc finger transcription factor GATA4, resulting in synergistic activation of cardiac transcription. Transgenic mice that express activated forms of calcineurin or NF-AT3 in the heart develop cardiac hypertrophy and heart failure that mimic human heart disease. Pharmacologic inhibition of calcineurin activity blocks hypertrophy in vivo and in vitro. These results define a novel hypertrophic signaling pathway and suggest pharmacologic approaches to prevent cardiac hypertrophy and heart failure.
Molkentin
J D
JD
Department of Molecular Biology and Oncology, The University of Texas Southwestern Medical Center at Dallas, 75225-9148, USA.
Lu
J R
JR
Antos
C L
CL
Markham
B
B
Richardson
J
J
Robbins
J
J
Grant
S R
SR
Olson
E N
EN
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000235:genetics; D019703:Calcineurin / Q000235:genetics / Q000502:physiology*; D006332:Cardiomegaly / Q000201:enzymology / Q000235:genetics* / Q000517:prevention & control; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D050991:GATA4 Transcription Factor; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D050778:NFATC Transcription Factors; D020097:Natriuretic Peptide, Brain; D009687:Nuclear Proteins; D010656:Phenylephrine / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000502:physiology*; D016335:Zinc Fingers
D004268:DNA-Binding Proteins; D050991:GATA4 Transcription Factor; D007166:Immunosuppressive Agents; D050778:NFATC Transcription Factors; C494010:NFATC4 protein, human; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D010656:Phenylephrine; D009320:Atrial Natriuretic Factor; D019703:Calcineurin