(Circulation. 2000;102:2751.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Physiological Induction of a ß-Adrenergic Receptor Kinase Inhibitor Transgene Preserves ß-Adrenergic Responsiveness in Pressure-Overload Cardiac Hypertrophy
From the Departments of Surgery (B.S.M., K.S., W.J.K.) and Medicine (L.M., H.A.R.), Duke University Medical Center, Durham, NC. Dr Manning is currently with Obesity Molecular Sciences, CVMD Discovery, Pfizer Global Research and Development, Groton Laboratories, Groton, Conn.
Correspondence to Walter J. Koch, PhD, Duke University Medical Center, Box 2606, Room 472 MSRB, Durham, NC 27710. E-mail koch0002{at}mc.duke.edu
Background—Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the ß-adrenergic receptor kinase (ßARKct) have increased in vivo cardiac function and enhanced ß-adrenergic receptor (ßAR) responsiveness.
Methods and Results—In the present study, we created transgenic mice with myocardium-targeted ßARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-ßARKct transgenic mice have normal in vivo cardiac contractility and ßAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-ßARKct hearts had elevations in left ventricular mass similar to those in NLCs; however, TAC did induce demonstrable ßARKct expression in the transgenic hearts. TAC in NLC mice resulted in an upregulation of myocardial ßARK1 and a loss of ßAR-mediated inotropic reserve. Importantly, although ßARK1 was increased in the hypertrophic CARP-ßARKct mice, the in vivo loss of ßAR responsiveness was not seen after induced ßARKct expression.
Conclusions—These results demonstrate that acute ßARK1 inhibition can restore lost myocardial ßAR responsiveness and inotropic reserve in vivo. Furthermore, these mice demonstrate the novel utility of the CARP promoter as an inducible element responsive to pathophysiological conditions in the adult heart.
Key Words: receptors, adrenergic, beta • hypertrophy • genetics
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