Myocardial transcription factors are modulated during pathologic cardiac hypertrophy in vivo.
OBJECTIVE
In the current study we describe and characterize a novel ovine model of biventricular hypertrophy and heart failure and evaluate the role of selected cardiac transcription factors in the regulation of cardiac gene expression during pathologic hypertrophy in vivo. The cardiac troponin T promoter is used as a model gene.


RESULTS
Transient transfections of ovine cardiomyocytes in culture show that Sp1, transcriptional enhancer factor-1, and myocyte enhancer factor-2 activate cardiac troponin T promoter constructs. Cotransfection of Sp3 inhibits cardiac troponin T promoter activity and represses Sp1-mediated activation of the cardiac troponin T promoter. By chromatin immunoprecipitation, transcriptional enhancer factor-1, myocyte enhancer factor-2, NKX2.5, GATA-4, and Sp factors bind the cardiac troponin T promoter in vivo. To assess the role of cardiac transcription during pathologic hypertrophy, in vivo, we created surgical aorta-pulmonary shunts in utero in fetal lambs. Two weeks after spontaneous delivery, shunted lambs showed failure to thrive, significant biventricular hypertrophy, and heart failure. Shunted hearts had significant increases in myosin and cardiac troponin T protein expression. There was a shift in expression to the high-molecular-weight fetal isoforms. Transcriptional enhancer factor-1, myocyte enhancer factor-2, GATA-4, NKX2.5, and Sp1 transcription factor levels were increased in all heart chambers of shunted animals. Sp3 expression was decreased in shunted ventricles. Immunoprecipitated Sp3 was associated with significant increases in histone acetyl transferase activity and decreases in histone-deacetylase activity.


CONCLUSIONS
The shunted neonatal lamb is a valid, novel model of pathologic biventricular hypertrophy. During pathologic hypertrophy myocardial transactivators are upregulated while repressors are downregulated.
Azakie
Anthony
A
University of California, San Francisco, Department of Surgery, San Francisco, Calif 94143, USA. azakiet@surgery.ucsf.edu
Fineman
Jeffrey R
JR
He
Youping
Y
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics; D050991:GATA4 Transcription Factor / Q000235:genetics; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics; D009206:Myocardium; D032383:Myocytes, Cardiac; D009687:Nuclear Proteins / Q000235:genetics; D012756:Sheep; D016329:Sp1 Transcription Factor / Q000235:genetics; D051705:Sp3 Transcription Factor / Q000235:genetics; D000091262:TEA Domain Transcription Factors; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C098771:DTEF-1 protein, Gallus gallus; D050991:GATA4 Transcription Factor; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C095552:NKX2-5 protein, human; D009687:Nuclear Proteins; D016329:Sp1 Transcription Factor; D000091262:TEA Domain Transcription Factors; C057182:TEAD1 protein, human; D014157:Transcription Factors; D051705:Sp3 Transcription Factor