The mechanisms responsible for the transition from stable compensated hypertrophy to myocardial dysfunction are not well understood. Several hypotheses have been suggested to be responsible for the progression of myocardial dysfunction including: alterations in Ca++ availability, abnormalities in the myocyte cytoskeleton such as microtubular polymerization, decreased volume fraction of cardiomyocyte myofibrils, and aberrations in beta-adrenergic receptor (beta-AR) signaling. In this regard, an important characteristic of human heart failure is diminished beta-AR number (receptor down regulation) and impaired beta-AR function (receptor uncoupling). Recent data suggest a step-wise increase in plasma norepinephrine levels in individuals from normal to asymptomatic left ventricular (LV) dysfunction and to symptomatic LV failure. Thus high levels of circulating catecholamines early in the transition from stable cardiac hypertrophy to Lv dysfunction, may account, in part, for the observed loss in beta-AR function. it therefore becomes apparent that abnormalities in beta-AR signaling are potential key targets, that if corrected, may interrupt the gradual deterioration of myocardial function in the clinical course of heart failure. The overall goal of this project is to use mouse genetics to specifically inhibit betaARK or to chronically enhance myocyte contractility during the transition from stable hypertrophy to decompensated dilated cardiomyopathy followed by a comprehensive biochemical, molecular and physiological analysis of beta-AR signaling and cardiac function. Studies are proposed to test the hypothesis that beta-adrenergic receptor desensitization early in the time course of a cardiomyopathy contributes to the progressive deterioration in contractile function, and that correction of the gene defect using mouse genetics can modify or even ameliorate the disease phenotype.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046345-09
Application #
6336645
Study Section
Project Start
2000-08-01
Project End
2001-07-31
Budget Start
1997-10-01
Budget End
1998-09-30
Support Year
9
Fiscal Year
2000
Total Cost
$278,736
Indirect Cost
Name
University of California San Diego
Department
Type
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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Bang, Marie-Louise; Gu, Yusu; Dalton, Nancy D et al. (2014) The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload. PLoS One 9:e93638
Israeli-Rosenberg, Sharon; Manso, Ana Maria; Okada, Hideshi et al. (2014) Integrins and integrin-associated proteins in the cardiac myocyte. Circ Res 114:572-586

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