Early and delayed consequences of β₂-adrenergic receptor overexpression in mouse hearts: Critical role for expression level

Background - Transgenic cardiac β₂-adrenergic receptor (AR) overexpression has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G(αs) or β₁AR have resulted in phenotypes of ventricular failure. Potential relationships between the levels of βAR overexpression and biochemical, molecular, and physiological consequences have not been reported. Methods and Results - We generated transgenic mice expressing β₂AR at 3690, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background βAR 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/dt(max) to nontransgenic levels in all β₂AR transgenics except the 350-fold overexpressors, indicating that spontaneous activation of β₂AR was present at this level of expression. Conclusions - These data demonstrate that the heart tolerates enhanced contractile function via 60-fold β₂AR 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 βAR function in the heart appear to be highly dependent on which signaling elements are increased and to what extent.