The proto-oncogene c-myc is one of several growth-regulated genes that are induced within the myocardium during the early stages following hemodynamic overload. While it has long been known that c-myc plays an important but undefined role in the regulation of cellular proliferation, recent evidence suggests that c-myc is a transcriptional factor and it would seem likely that the c-myc gene product modulates at least some of the qualitative and quantitative changes in gene expression that characterize the hypertrophying myocyte. We have developed a feline model of gradual and progressive pressure-overload which mimics human disease in its ongoing nature. In contrast to the transient increases in c-myc mRNA that are typical of acute pressure-overload, hearts isolated from these animals show sustained increases in steady-state levels of c-myc mRNA and immuno-reactive myc protein. This unique animal model, which closely mimics the nature and progression of human disease, is highly suitable for the study of factors that regulate c-myc gene expression in hemodynamic overload in vivo.
The Specific Aims of this proposal are to: 1 . Characterize the time course of increased levels of c-myc in progressive pressure-overload and determine if the increases in steady-state c-myc mRNA are due to alterations in promoter usage in progressive pressure overload. 2 . Determine if overexpression of c-myc can be associated with an increase in those indices of cell growth considered characteristic of cardiac hypertrophy. 3 . Compare the rates of c-myc transcription in pressure-overloaded myocytes with those of control cells. 4.Begin to identify regulatory regions of the myc gene that modulate c-myc gene expression in response to a hypertrophic stimulus. Heart failure, frequently the end result of chronic hemodynamic overload, remains a significant source of morbidity and mortality in this country. The cellular and molecular mechanisms that regulate the development of hypertrophy in the pressure-overloaded cardiac myocyte are still poorly understood. Determining the mechanisms by which c-myc gene expression is regulated in pressure-overload hypertrophy will be the first step to the accomplishment of the long term aim of this research. This is the identification of the signal transduction mechanisms that are responsible for the linking of a hemodynamic stimulus to the induction of c-myc and other transcriptional regulators.
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