Adenoviral-mediated gene transfer of a βARK1 inhibitor (βARKct) or human β2-AR to failing rabbit ventricular myocytes restored β-adrenergic signaling, significantly increasing cAMP production.
Does adenoviral-mediated gene transfer of human beta2-AR or a betaARK1 inhibitor restore beta-adrenergic signaling in isolated ventricular myocytes from rabbits with pacing-induced heart failure?
Demonstrates in vitro that genetic modification can correct beta-adrenergic signaling defects in failing myocardium, highlighting betaARK1 inhibition as a potential novel therapy for heart failure.
Absolute Event Rate: 1.9% vs 0.8%
p-value: p=<0.05
Cardiovascular gene therapy is a novel approach to the treatment of diseases such as congestive heart failure (CHF). Gene transfer to the heart would allow for the replacement of defective or missing cellular proteins that may improve cardiac performance. Our laboratory has been focusing on the feasibility of restoring beta-adrenergic signaling deficiencies that are a characteristic of chronic CHF. We have now studied isolated ventricular myocytes from rabbits that have been chronically paced to produce hemodynamic failure. We document molecular beta-adrenergic signaling defects including down-regulation of myocardial beta-adrenergic receptors (beta-ARs), functional beta-AR uncoupling, and an up-regulation of the beta-AR kinase (betaARK1). Adenoviral-mediated gene transfer of the human beta2-AR or an inhibitor of betaARK1 to these failing myocytes led to the restoration of beta-AR signaling. These results demonstrate that defects present in this critical myocardial signaling pathway can be corrected in vitro using genetic modification and raise the possibility of novel inotropic therapies for CHF including the inhibition of betaARK1 activity in the heart.
Akhter et al. (Tue,) conducted a other in Congestive heart failure (rabbit model). Adenoviral-mediated gene transfer of human β2-AR or βARKct vs. Empty adenoviral vector (empty Ad5) was evaluated on Basal intracellular cAMP accumulation (% conversion) (p=<0.05). Adenoviral-mediated gene transfer of a βARK1 inhibitor (βARKct) or human β2-AR to failing rabbit ventricular myocytes restored β-adrenergic signaling, significantly increasing cAMP production.