Physiological induction of a β-adrenergic receptor kinase inhibitor transgene preserves β-adrenergic responsiveness in pressure-overload cardiac hypertrophy

Abstract

Background - Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the β-adrenergic receptor kinase (βARKct) have increased in vivo cardiac function and enhanced β-adrenergic receptor (βAR) responsiveness. Methods and Results - In the present study, we created transgenic mice with myocardium-targeted βARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-βARKct transgenic mice have normal in vivo cardiac contractility and βAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-βARKct hearts had elevations in left ventricular mass similar to those in NLCs; however, TAC did induce demonstrable βARKct expression in the transgenic hearts. TAC in NLC mice resulted in an upregulation of myocardial βARK1 and a loss of βAR-mediated inotropic reserve. Importantly, although βARK1 was increased in the hypertrophic CARP-βARKct mice, the in vivo loss of βAR responsiveness was not seen after induced βARKct expression. Conclusions - These results demonstrate that acute βARK1 inhibition can restore lost myocardial βAR responsiveness and inotropic reserve in vivo. Furthermore, these mice demonstrate the novel utility of the CARP promoter as an inducible element responsive to pathophysiological conditions in the adult heart.