Electrical stimulation of neonatal cardiac myocytes activates the NFAT3 and GATA4 pathways and up-regulates the adenylosuccinate synthetase 1 gene.
Electrically stimulated pacing of cultured cardiomyocytes serves as an experimentally convenient and physiologically relevant in vitro model of cardiac hypertrophy. Electrical pacing triggers a signaling cascade that results in the activation of the muscle-specific Adss1 gene and the repression of the nonmuscle Adss2 isoform. Activation of the Adss1 gene involves the calcineurin-mediated dephosphorylation of NFAT3, allowing its translocation to the nucleus, where it can directly participate in Adss1 gene activation. Mutational studies show that an NFAT binding site located in the Adss1 5'-flanking region is essential for this activation. Electrical pacing also results in the increased synthesis of GATA4, another critical cardiac transcription factor required for Adss1 gene expression. MEF2C also produces transactivation of the Adss1 gene reporter in control and paced cardiac myocytes. Using the Adss1 gene as a model, these studies are the first to demonstrate that electrical pacing activates the calcineurin/NFAT3 and GATA4 pathways as a means of regulating cardiac gene expression.
Xia
Y
Y
Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, Texas 77030, USA.
McMillin
J B
JB
Lewis
A
A
Moore
M
M
Zhu
W G
WG
Williams
R S
RS
Kellems
R E
RE
D000265:Adenylosuccinate Synthase / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D015152:Blotting, Northern; D019703:Calcineurin / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D015500:Chloramphenicol O-Acetyltransferase / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050991:GATA4 Transcription Factor; D005786:Gene Expression Regulation; D015971:Gene Expression Regulation, Enzymologic; D064326:MEF2 Transcription Factors; D009206:Myocardium / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D015854:Up-Regulation
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D020033:Protein Isoforms; D014157:Transcription Factors; D016572:Cyclosporine; D015500:Chloramphenicol O-Acetyltransferase; D019703:Calcineurin; D000265:Adenylosuccinate Synthase