(Circulation. 1999;100:648-653.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
In Vivo Inhibition of Elevated Myocardial ß-Adrenergic Receptor Kinase Activity in Hybrid Transgenic Mice Restores Normal ß-Adrenergic Signaling and Function
From the Departments of Surgery (S.A.A., A.D.E., K.S., W.J.K.) and Medicine and Biochemistry and the Howard Hughes Medical Institute (R.J.L.), Duke University Medical Center, Durham, NC, and the Department of Medicine/Cardiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC (H.A.R.).
Correspondence to Walter J. Koch, PhD, Laboratory of Molecular Cardiovascular Biology, Box 2606, MSRB Room 471, Duke University Medical Center, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac ß-adrenergic receptor (ßAR) system, which is critical in the regulation of myocardial function. Expression of the ßAR kinase (ßARK1), which phosphorylates and uncouples ßARs, is elevated in human HF; this likely contributes to the abnormal ßAR responsiveness that occurs with ß-agonist administration. We previously showed that transgenic mice with increased myocardial ßARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous ßARK1 activity in the heart led to enhanced myocardial function.
Methods and Results—We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both ßARK1 and an inhibitor of ßARK1 activity to study the feasibility and functional consequences of the inhibition of elevated ßARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of ßARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial ßARK1 levels remained elevated due to transgene expression, in vitro ßARK1 activity returned to control levels and the percentage of ßARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to ßAR stimulation was restored to normal in the hybrid double-transgenic mice.
Conclusions—Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial ßARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac ßARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.
Key Words: receptors, adrenergic, beta • G proteins • protein kinases • desensitization • heart failure • mice, transgenic • myocardium
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