Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice.
Abstract
Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR)
function, which includes loss of betaAR density and functional uncoupling of remaining
receptors. An important mechanism for the rapid desensitization of betaAR function
is agonist-stimulated receptor phosphorylation by the betaAR kinase (betaARK1), an
enzyme known to be elevated in failing human heart tissue. To investigate whether
alterations in betaAR function contribute to the development of myocardial failure,
transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor
of betaARK1 or the beta2AR were mated into a genetic model of murine heart failure
(MLP-/-). In vivo cardiac function was assessed by echocardiography and cardiac catheterization.
Both MLP-/- and MLP-/-/beta2AR mice had enlarged left ventricular (LV) chambers with
significantly reduced fractional shortening and mean velocity of circumferential fiber
shortening. In contrast, MLP-/-/betaARKct mice had normal LV chamber size and function.
Basal LV contractility in the MLP-/-/betaARKct mice, as measured by LV dP/dtmax, was
increased significantly compared with the MLP-/- mice but less than controls. Importantly,
heightened betaAR desensitization in the MLP-/- mice, measured in vivo (responsiveness
to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase
activity), was completely reversed with overexpression of the betaARK1 inhibitor.
We report here the striking finding that overexpression of this inhibitor prevents
the development of cardiomyopathy in this murine model of heart failure. These findings
implicate abnormal betaAR-G protein coupling in the pathogenesis of the failing heart
and point the way toward development of agents to inhibit betaARK1 as a novel mode
of therapy.
Type
Journal articleSubject
AnimalsCyclic AMP-Dependent Protein Kinases
Enzyme Inhibitors
G-Protein-Coupled Receptor Kinase 2
Gene Targeting
Gene Transfer Techniques
Heart Failure
Humans
Mice
Mice, Transgenic
beta-Adrenergic Receptor Kinases
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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 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
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
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