Heart failure is a serious health problem in the United States accounting 550,000 new cases annually with an estimated cost of $28 billion in 2005. Despite major advances in the diagnosis and treatment of this disease, mortality level is unacceptably high. New therapeutic modalities, preventing and/or correcting the progression of disease, are needed. The major objective of this proposal is to investigate the role of the transcription factor c-Fos in the development and progression of myocardial hypertrophy and dysfunction. Abrogating c-Fos with a dominant negative strategy (AFos) in neonatal rat ventricular myocytes resulted in the reversal of the fetal gene program while preserving agonist induced growth. This finding indicates that gene expression and growth may not be obligate processes as once thought. The remaining question is: what is the functional capacity of these agonist driven hypertrophic myocytes when gene expression is reversed by transcriptional methods? The primary hypothesis is that cardiac specific inhibition of c-Fos in the setting of pathologic hypertrophic stimuli will result in a more physiologic growth response, and the functional deterioration seen in pathologic hypertrophy will be ameliorated or reversed. The rationale for such an approach is that this could result in novel therapeutic options for heart failure that would complement and extend current treatment modalities to this devastating syndrome. To that end, the following specific aims are proposed.
Specific Aim 1 : Examine the effect of AFos on the hypertrophic growth and gene program responses of cultured adult rat ventricular myocyte to hypertrophic stimuli. With the improvement in the gene program, study the contractile properties of individual myoctes to determine the role of gene expression on function. Additionally, examine the level and function of key proteins in response to the altered gene expression.
Specific Aim 2 : Determine if transgenic mice lacking the action of c-Fos alters the response to physiologic and pathologic hypertrophic stimuli. Tet-Off AFos mice will be subjected to either thoracic aortic banding or voluntary wheeling running and compared to control animals. These mice will be studied with serial echocardiography, and genetic, histologic, and morphologic changes in the heart at key time points will be evaluated. At the conclusion of this project, the role of c-Fos in the development of myocardial hypertrophy and progression to contractile dysfunction will be better elucidated. ? ? ? ?
| Jeong, Mark Y; Walker, John S; Brown, R Dale et al. (2010) AFos inhibits phenylephrine-mediated contractile dysfunction by altering phospholamban phosphorylation. Am J Physiol Heart Circ Physiol 298:H1719-26 |
