In vivo inhibition of elevated myocardial beta-adrenergic receptor kinase activity in hybrid transgenic mice restores normal beta-adrenergic signaling and function

Background-The clinical syndrome of heart failure (KF) is characterized by an impaired cardiac beta-adrenergic receptor (PAR) system, which is critica l in the regulation of myocardial function. Expression of the beta AR kinas e (beta ARK1), which phosphorylates and uncouples beta ARs, is elevated in human EFF; this likely contributes to the abnormal PAR responsiveness that occurs with beta-agonist administration. We previously showed that transgen ic mice with increased myocardial beta ARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous beta ARK1 activity in the heart led to enhanced myocardial function. Methods and Results-We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both beta ARK1 and an inhibitor of beta ARK1 activity to study the feasibility and functional consequences of the inhib ition of elevated beta ARK1 activity similar to that present in human HF. T ransgenic mice with myocardial overexpression of beta ARK1 (3 to 5-fold) ha ve a blunted in vivo contractile response to isoproterenol when compared wi th non-transgenic control mice. In the hybrid transgenic mice, although myo cardial beta ARK1 levels remained elevated due to transgene expression, in vitro beta ARK1 activity returned to control levels and the percentage of b eta ARs in the high-affinity state increased to normal wild-type levels. Fu rthermore, the in vivo left ventricular contractile response to beta AR sti mulation was restored to normal in the hybrid double-transgenic mice. Conclusions-Novel hybrid transgenic mice can be created with concomitant ca rdiac-specific overexpression of 2 independent transgenes with opposing act ions. Elevated myocardial beta ARK1 in transgenic mouse hearts (to levels s een in human HF) can be inhibited in vive by a peptide that can, prevent ag onist-stimulated desensitization of cardiac beta ARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.