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Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein.

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Date
1996-04-01
Authors
Rockman, HA
Hamilton, RA
Jones, LR
Milano, CA
Mao, L
Lefkowitz, RJ
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Abstract
To assess the effect of targeted myocardial beta-adrenergic receptor (AR) stimulation on relaxation and phospholamban regulation, we studied the physiological and biochemical alterations associated with overexpression of the human beta2-AR gene in transgenic mice. These mice have an approximately 200-fold increase in beta-AR density and a 2-fold increase in basal adenylyl cyclase activity relative to negative littermate controls. Mice were catheterized with a high fidelity micromanometer and hemodynamic recordings were obtained in vivo. Overexpression of the beta2-AR altered parameters of relaxation. At baseline, LV dP/dt(min) and the time constant of LV pressure isovolumic decay (Tau) in the transgenic mice were significantly shorter compared with controls, indicating markedly enhanced myocardial relaxation. Isoproterenol stimulation resulted in shortening of relaxation velocity in control mice but not in the transgenic mice, indicating maximal relaxation in these animals. Immunoblotting analysis revealed a selective decrease in the amount of phospholamban protein, without a significant change in the content for either sarcoplasmic reticulum Ca2+ ATPase or calsequestrin, in the transgenic hearts compared with controls. This study indicates that myocardial relaxation is both markedly enhanced and maximal in these mice and that conditions associated with chronic beta-AR stimulation can result in a selective reduction of phospholamban protein.
Type
Journal article
Subject
Animals
Calcium-Binding Proteins
Calcium-Transporting ATPases
Calsequestrin
Hemodynamics
Humans
Mice
Mice, Transgenic
Myocardial Contraction
Myocardium
Phenotype
Receptors, Adrenergic, beta-2
Sarcoplasmic Reticulum
Permalink
https://hdl.handle.net/10161/5929
Published Version (Please cite this version)
10.1172/JCI118587
Publication Info
Rockman, HA; Hamilton, RA; Jones, LR; Milano, CA; Mao, L; & Lefkowitz, RJ (1996). Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein. J Clin Invest, 97(7). pp. 1618-1623. 10.1172/JCI118587. Retrieved from https://hdl.handle.net/10161/5929.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Lefkowitz

Robert J. Lefkowitz

The Chancellor's Distinguished Professor of Medicine
Dr. Lefkowitz’s memoir, A Funny Thing Happened on the Way to Stockholm, recounts his early career as a cardiologist and his transition to biochemistry, which led to his Nobel Prize win. Robert J. Lefkowitz, M.D. is James B. Duke Professor of Medicine and Professor of Biochemistry and Chemistry at the Duke University Medical Center. He has been an Investigator of the

Lan Mao

Assistant Professor in Medicine
I. Research: As the director of mouse physiology laboratory, in charge for the all events related with Dr. Howard Rockman's molecular biology laboratory studies needs. Participate in research in rodents model: Perform surgery and serve as co-investigator in studies on transgenic mice with heart failure. Develop models of hypertrophy in small animal using micro-surgical techniques (aortic constriction, left ventricular infarction and abdominal aortocaval fistula) and perform
Milano

Carmelo Alessio Milano

Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery
Rockman

Howard Allan Rockman

Edward S. Orgain Distinguished Professor of Cardiology, in the School of Medicine
Rockman Lab: Molecular Mechanisms of Hypertrophy and Heart Failure Overall Research Direction: The major focus of this laboratory is to understand the molecular mechanisms of hypertrophy and heart failure. My laboratory uses a strategy that combines state of the art molecular techniques to generate transgenic and gene targeted mouse models, combined with sophisticated physiologic measures of in vivo cardiac function. In this manner, candidate molecules are either selectively overexp
Alphabetical list of authors with Scholars@Duke profiles.
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