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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32HL067609-02
Application #
6527907
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Commarato, Michael
Project Start
2002-08-01
Project End
2002-08-31
Budget Start
2002-08-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$6,141
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Young, Martin E; Guthrie, Patrick H; Razeghi, Peter et al. (2002) Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes 51:2587-95
Razeghi, Peter; Young, Martin E; Cockrill, Tonya C et al. (2002) Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106:407-11
Taegtmeyer, Heinrich; McNulty, Patrick; Young, Martin E (2002) Adaptation and maladaptation of the heart in diabetes: Part I: general concepts. Circulation 105:1727-33
Young, Martin E; Wilson, Christopher R; Razeghi, Peter et al. (2002) Alterations of the circadian clock in the heart by streptozotocin-induced diabetes. J Mol Cell Cardiol 34:223-31
Young, Martin E; McNulty, Patrick; Taegtmeyer, Heinrich (2002) Adaptation and maladaptation of the heart in diabetes: Part II: potential mechanisms. Circulation 105:1861-70
Young, M E; Laws, F A; Goodwin, G W et al. (2001) Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart. J Biol Chem 276:44390-5