Myocardial Transcription Factors Are Modulated During Pathologic Cardiac Hypertrophy In Vivo- Identifying Potential Targets For Pharmaco-therapy Of Heart Failure
Back to 86th Annual Meeting
Back to Program Outline
Objective: Pathologic cardiac hypertrophy and heart failure are associated with cardiac remodeling, reprogramming of cardiac gene expression and activation of fetal/embryonic genes. Targetting cardiac transcription to normalize cardiac gene expression may provide a strategy to prevent heart failure. In the current study we evaluate the role of cardiac transcription factors (GATA-4, TEF-1, MEF-2, NKx2.5, and Sp1 family) in the regulation of cardiac gene expression during development and pathologic hypertrophy, in vivo. We use the cardiac troponin T promoter as a model gene.
Methods and Results: By chromatin immunoprecipitation (IP), GATA-4, TEF-1, MEF-2, NKx2.5, and Sp factors bind the cardiac Troponin T (cTnT) promoter in vivo. Transient transfections of embryonic cardiac myocytes shows that Sp1, TEF-1, MEF-2 activate the cTnT promoter. Cotransfection of Sp3 produces inhibition of cTnT promoter activity, and represses Sp1-mediated activation of the cTnT promoter. In order to assess the role of cardiac transcription during pathologic hypertrophy, in vivo, an animal model of pathologic biventricular hypertrophy was established. Surgical aortopulmonary shunts were created in fetal lambs (n=5) that produced significant biventricular hypertrophy after 2-weeks of shunting. By western blot analysis shunted hearts had significant increases in myosin and cTnT protein expression within both atria and ventricles and there was a shift in expression to the high molecular weight fetal isoforms. Consistent with their trans-activating function, GATA-4, MEF-2, TEF-1 and Sp1 levels were increased in all chambers of shunted animals. There was a decrease in Sp3 expression levels in shunted ventricles, consistent with Sp3's inhibitory effects on cardiac promoter activity. During cardiac hypertrophy, immunoprecipitated Sp3 was associated with significant increases in histone acetyl transferase activity and decreases in histone-deacetylase activity.
Conclusion: Sp factor levels are modulated during pathologic cardiac hypertrophy. Sp3 is acetylated during hypertrophy and may provide a pharmacologic target and mechanism for prevention of pathologic hypertrophy by Histone Deacetylase inhibitors.
Back to 86th Annual Meeting
Back to Program Outline
