doi: 10.1161/hc4501.098933
(Circulation. 2001;104:2485.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Augmentation of Cardiac Contractility Mediated by the Human ß3-Adrenergic Receptor Overexpressed in the Hearts of Transgenic Mice
From Howard Hughes Medical Institute, Departments of Medicine (T.A.K., H.T., P.H.M., S.J.P., L.M., R.J.L., H.A.R.), Cell Biology (H.T., L.M., H.A.R.), and Biochemistry (T.A.K., P.H.M., S.J.P., R.J.L.), Duke University Medical Center, Durham, NC.
Correspondence to Robert J. Lefkowitz, MD, Howard Hughes Medical Institute, Departments of Medicine and Biochemistry, Duke University Medical Center, Box 3821, Durham, NC 27710. E-mail lefko001{at}receptor-biol.duke.edu
Background— Stimulation of ß1- and ß2-adrenergic receptors (ARs) in the heart results in positive inotropy. In contrast, it has been reported that the ß3AR is also expressed in the human heart and that its stimulation leads to negative inotropic effects.
Methods and Results— To better understand the role of ß3ARs in cardiac function, we generated transgenic mice with cardiac-specific overexpression of 330 fmol/mg protein of the human ß3AR (TGß3 mice). Hemodynamic characterization was performed by cardiac catheterization in closed-chest anesthetized mice, by pressure-volume-loop analysis, and by echocardiography in conscious mice. After propranolol blockade of endogenous ß1- and ß2ARs, isoproterenol resulted in an increase in contractility in the TGß3 mice (30%), with no effect in wild-type mice. Similarly, stimulation with the selective human ß3AR agonist L-755,507 significantly increased contractility in the TGß3 mice (160%), with no effect in wild-type mice, as determined by hemodynamic measurements and by end-systolic pressure-volume relations. The underlying mechanism of the positive inotropy incurred with L-755,507 in the TGß3 mice was investigated in terms of ß3AR–G-protein coupling and adenylyl cyclase activation. Stimulation of cardiac membranes from TGß3 mice with L-755,507 resulted in a pertussis toxin–insensitive 1.33-fold increase in [35S]GTP
S loading and a 1.6-fold increase in adenylyl cyclase activity.
Conclusions— Cardiac overexpression of human ß3ARs results in positive inotropy only on stimulation with a ß3AR agonist. Overexpressed ß3ARs couple to Gs and activate adenylyl cyclase on agonist stimulation.
Key Words: signal transduction • pharmacology • gene therapy • inotropic agents
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