(Circulation. 2000;101:1707.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Early and Delayed Consequences of ß2-Adrenergic Receptor Overexpression in Mouse Hearts
Critical Role for Expression Level
From the Departments of Medicine (S.B.L., A.M.C., T.D.J., G.W.D.) and Pharmacology (S.B.L., N.M.T., J.N.L., S.M., A.Y., G.W.D.), University of Cincinnati Medical Center, Cincinnati, Ohio.
Correspondence to G.W. Dorn II, University of Cincinnati Medical Center, 231 Bethesda Ave, ML 0590, Cincinnati, OH 45267-0590. E-mail dorngw{at}ucmail.uc.edu
Background—Transgenic cardiac
ß2-adrenergic receptor (AR) overexpression has resulted
in enhanced signaling and cardiac function in mice, whereas relatively
low levels of transgenically expressed G
s or
ß1AR have resulted in phenotypes of
ventricular failure. Potential relationships between the
levels of ßAR overexpression and biochemical, molecular, and
physiological consequences have not been
reported.
Methods and Results—We generated transgenic mice expressing ß2AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background ßAR expression. All lines showed enhanced basal adenylyl cyclase activation but a decrease in forskolin- and NaF-stimulated adenylyl cyclase activities. Mice of the highest-expressing line developed a rapidly progressive fibrotic dilated cardiomyopathy and died of heart failure at 25±1 weeks of age. The 60-fold line exhibited enhanced basal cardiac function without increased mortality when followed for 1 year, whereas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart failure, with death occurring at 41±1 weeks of age. Adenylyl cyclase activation did not correlate with early or delayed decompensation. Propranolol administration reduced baseline +dP/dtmax to nontransgenic levels in all ß2AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of ß2AR was present at this level of expression.
Conclusions—These data demonstrate that the heart tolerates
enhanced contractile function via 60-fold ß2AR
overexpression without detriment for a period of 
1 year and that
higher levels of expression result in either aggressive or delayed
cardiomyopathy. The consequences for enhanced ßAR
function in the heart appear to be highly dependent on which signaling
elements are increased and to what extent.
Key Words: receptors, adrenergic, beta • cardiomyopathy • heart failure
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