In Vivo Inhibition of Elevated Myocardial β-Adrenergic Receptor Kinase Activity in Hybrid Transgenic Mice Restores Normal β-Adrenergic Signaling and Function

Abstract

Background —The clinical syndrome of heart failure (HF) is characterized by an impaired cardiac β-adrenergic receptor (βAR) system, which is critical in the regulation of myocardial function. Expression of the βAR kinase (βARK1), which phosphorylates and uncouples βARs, is elevated in human HF; this likely contributes to the abnormal βAR responsiveness that occurs with β-agonist administration. We previously showed that transgenic mice with increased myocardial βARK1 expression had impaired cardiac function in vivo and that inhibiting endogenous βARK1 activity in the heart led to enhanced myocardial function. Methods and Results —We created hybrid transgenic mice with cardiac-specific concomitant overexpression of both βARK1 and an inhibitor of βARK1 activity to study the feasibility and functional consequences of the inhibition of elevated βARK1 activity similar to that present in human HF. Transgenic mice with myocardial overexpression of βARK1 (3 to 5-fold) have a blunted in vivo contractile response to isoproterenol when compared with non-transgenic control mice. In the hybrid transgenic mice, although myocardial βARK1 levels remained elevated due to transgene expression, in vitro βARK1 activity returned to control levels and the percentage of βARs in the high-affinity state increased to normal wild-type levels. Furthermore, the in vivo left ventricular contractile response to βAR stimulation was restored to normal in the hybrid double-transgenic mice. Conclusions —Novel hybrid transgenic mice can be created with concomitant cardiac-specific overexpression of 2 independent transgenes with opposing actions. Elevated myocardial βARK1 in transgenic mouse hearts (to levels seen in human HF) can be inhibited in vivo by a peptide that can prevent agonist-stimulated desensitization of cardiac βARs. This may represent a novel strategy to improve myocardial function in the setting of compromised heart function.