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J Thorac Cardiovasc Surg 2006;132:1262-1271
© 2006 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Myocardial transcription factors are modulated during pathologic cardiac hypertrophy in vivo

Anthony Azakie, MDa,b,*,*, Jeffrey R. Fineman, MDb, Youping He, PhDa

a University of California, San Francisco, Department of Surgery, San Francisco, Calif
b University of California, San Francisco, Department of Pediatrics, San Francisco, Calif.

Read at the Eighty-sixth Annual Meeting of The American Association for Thoracic Surgery, Philadelphia, Pa, April 29-May 3, 2006.

Received for publication April 27, 2006; revisions received June 30, 2006; accepted for publication August 10, 2006.

* Address for reprints: Anthony Azakie, MD, 513 Parnassus Ave, Room S-549, Box 0117, University of California San Francisco, San Francisco, CA 94143. (Email: azakiet{at}surgery.ucsf.edu).

OBJECTIVES: 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.

METHODS AND 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.

CONCLUSION: The shunted neonatal lamb is a valid, novel model of pathologic biventricular hypertrophy. During pathologic hypertrophy myocardial transactivators are upregulated while repressors are downregulated.

Abbreviations and Acronyms ADP = adenosine diphosphate; ChIP = chromatin immunoprecipitation; cTnT = cardiac troponin T; HAT = histone acetyl transferase; HDAC = histone deacetylase; MEF2 = myocyte enhancer factor 2; PAR = poly(adenosine diphosphate ribose); PARP = poly(adenosine diphosphate ribose) polymerase; TEF-1 = transcriptional enhancer factor-1


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J. Thorac. Cardiovasc. Surg. 2006 132: 1270-1271. [Extract] [Full Text] [PDF]



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