The adult mammalian heart has the capacity to modify its patterns of gene and protein expression in response to various hemodynamic loads and/or hormones. Pathologic and physiologic cardiac hypertrophy are two adaptations which develop in response to external stimuli and manifest distinct mechanical properties and patterns of myosin heavy chain gene expression. While these models of adaptive hypertrophy have been well defined, the hemodynamic or humoral signals which lead to altered patterns of gene expression are unknown and the spectrum of genes whose transcription is altered is not fully defined. Also unknown are the identity of genes in addition to myosin heavy chain whose expression (or repression) may be responsible for the transition from compensated to decompensated physiology. The hypothesis which underlies this proposal is that the activation of specific genes initiates the development of adaptive cardiac hypertrophy and that the expression of other genes is responsible for the maintenance or decompeneation of the adaptation. Our overall goals are to define the physiologic triggers which result in altered gene expression and to identify the genes whose expression 1) predicts and 2) ultimately determines the physiologic characteristics of adaptive cardiac hypertrophy. Two approaches will be used: first, we will employ subtracted cDNA probes as screens to identify genes selectively induced in intact animals exposed to pathologic and physiologic conditions; and secondly, we will use the perfused rat heart to isolate hemodynamic and humoral variables which might lead to altered gene expression. In addition, our long term goals include demonstrating, initially by co-transfection of myocytes, and eventually by creating transgenic animals, that the expression of target genes (such as myosin heavy chain) can be manipulated and that this in turn will change the physiology of adaptive hypertrophy.
NIH ExPorter
NIH ExPorter