verbatim): As a metabolic omnivore the heart is able to adapt to a variety of changes in its environment. For example, in response to sustained pressure overload, the cardiomyocytes increase protein synthesis, increase in size (hypertrophy), revert to a fetal pattern of gene expression, and rely increasingly on glucose as a fuel (while decreasing fatty acid utilization). The molecular mechanism by which this metabolic adaptation occurs are not completely understood. Here, we propose that intermediary glucose metabolites are the signal in the genomic adaptation of the myocardium to sustained environmental stimuli. More specifically, we hypothesize that glucose metabolites activate one or more ?glucose sensing? transcription factors, resulting in a uniform genomic response, including the re-expression of fetal genes (atrial natriuretic factor, myosin heavy chain beta (MHCbeta) and skeletal alpha actin), and the selective repression of adult genes, such as myosin heavy chain alpha (MHCalpha) and cardiac alpha actin. Our preliminary results suggest that MHCalpha, MHCbeta, skeletal alpha actin, and basic fibroblast growth factor are genes whose expression is regulated by glucose metabolites in response to hypertrophy. We now plan to identify all glucose-regulated genes, and the mechanisms of ?glucose sensing? in the heart. This includes the identification of transcription factors, and the mechanisms by which they become activated. We know already that Sp1 becomes activated during pressure overload induced hypertrophy, and our preliminary results show that a second known hepatic ?glucose-sensing? transcription factor, USF1, is activated in both the hypertrophic and diabetic heart. Through the use of both in vivo (heterotopic transplantation, aortic constriction and streptozotocin administration for the unloaded, pressure overloaded and diabetic models respectively) and in vitro (isolated working rat heart) models, the nature and dynamics of glucose-sensing in the heart will be defined. Once identified, the expression and activity of key factors involved in cardiac glucose sensing will be manipulated in vivo through the use of pharmacological agents, antisense oligonucleotides and transgenic animals. The results will either support or refute the hypothesis that glucose metabolites form a link between gene expression and function of the heart.
