Early and delayed consequences of beta(2)-adrenergic receptor overexpression in mouse hearts - Critical role for expression level

Background-Transgenic cardiac beta(2)-adrenergic receptor (AR) overexpressi on has resulted in enhanced signaling and cardiac function in mice, whereas relatively low levels of transgenically expressed G(alpha s) or beta(1)AR have resulted in phenotypes of ventricular failure. Potential relationships between the levels of PAR overexpression and biochemical, molecular, and p hysiological consequences have not been reported. Methods and Results-We generated transgenic mice expressing beta(2)AR at 36 90, 7120, 9670, and 23 300 fmol/mg in the heart, representing 60, 100, 150, and 350 times background beta AR expression. All lines showed enhanced bas al adenylyl cyclase activation but a decrease in forskolin- and NaF-stimula ted adenylyl cyclase activities. Mice of the highest-expressing line develo ped 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, wher eas 100-fold overexpressors developed a fibrotic cardiomyopathy and heart f ailure, with death occurring at 41+/-1 weeks of age. Adenylyl cyclase activ ation did not correlate with early or delayed decompensation. Propranolol a dministration reduced baseline +dP/dt(max) nontransgenic levels in all beta (2)R transgenics except the 350-fold overexpressors, indicating that sponta neous activation of beta(2)R was present at this level of expression. Conclusions-These data demonstrate that the heart tolerates enhanced contra ctile function via 60-fold beta(2)AR overexpression without detriment for a period of greater than or equal to 1 year and that higher levels of expres sion result in either aggressive or delayed cardiomyopathy. The consequence s for enhanced beta AR function in the heart appear to be highly dependent on which signaling elements an increased and to what extent.