Enhanced myocardial relaxation in vivo in transgenic mice overexpressing the beta2-adrenergic receptor is associated with reduced phospholamban protein.
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 articleSubject
AnimalsCalcium-Binding Proteins
Calcium-Transporting ATPases
Calsequestrin
Hemodynamics
Humans
Mice
Mice, Transgenic
Myocardial Contraction
Myocardium
Phenotype
Receptors, Adrenergic, beta-2
Sarcoplasmic Reticulum
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https://hdl.handle.net/10161/5929Published Version (Please cite this version)
10.1172/JCI118587Publication 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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Show full item recordScholars@Duke
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 Chancellor’s Distinguished Professor of Medicine and
Professor of Biochemistry and Chemistry at the Duke University Medical Center. He
has bee
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 a v
Carmelo Alessio Milano
Joseph W. and Dorothy W. Beard Distinguished Professor of Experimental Surgery
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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