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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29HL046034-04
Application #
2222651
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1994-01-01
Budget End
1994-12-31
Support Year
4
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Montefiore Medical Center (Bronx, NY)
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10467
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Fishman, G I; Kaplan, M L; Buttrick, P M (1994) Tetracycline-regulated cardiac gene expression in vivo. J Clin Invest 93:1864-8
De Leon, J R; Buttrick, P M; Fishman, G I (1994) Functional analysis of the connexin43 gene promoter in vivo and in vitro. J Mol Cell Cardiol 26:379-89
Kaplan, M L; Cheslow, Y; Vikstrom, K et al. (1994) Cardiac adaptations to chronic exercise in mice. Am J Physiol 267:H1167-73
Fisher, S A; Buttrick, P M; Sukovich, D et al. (1993) Characterization of promoter elements of the rabbit cardiac sarcoplasmic reticulum Ca(2+)-ATPase gene required for expression in cardiac muscle cells. Circ Res 73:622-8
Buttrick, P; Kaplan, M; Camargo, M J et al. (1993) The influence of dietary salt and plasma renin activity on myosin heavy chain gene expression in rat hearts. Am J Hypertens 6:579-85
Buttrick, P M; Kaplan, M L; Kitsis, R N et al. (1993) Distinct behavior of cardiac myosin heavy chain gene constructs in vivo. Discordance with in vitro results. Circ Res 72:1211-7
Geenen, D L; Malhotra, A; Buttrick, P M et al. (1992) Increased heart rate prevents the isomyosin shift after cardiac transplantation in the rat. Circ Res 70:554-8
Buttrick, P M; Kass, A; Kitsis, R N et al. (1992) Behavior of genes directly injected into the rat heart in vivo. Circ Res 70:193-8