Abstract 16596: Disruption of Gravin’s Scaffolding as a Potential Therapy for Heart Failure in Combination With Carvedilol

Abstract

Beta-adrenergic receptor (β-AR) desensitization culminating in impaired β-AR signaling triggers the vicious cascade of HF. Gravin; an A-kinase anchoring protein (AKAP) is crucial for desensitization of the β-ARs upon agonist stimulation. Our previous studies have shown that disruption of gravin’s scaffolding imparts protection against isoproterenol induced HF in mice. The goal of this study was to further compare the protective effects of absence of gravin in HF to that of the standard β blocker HF therapy such as Carvedilol and Bisoprolol. After inducing HF with 2-weeks administration of isoproterenol (60mg/kg/day), wild-type (WT) and gravin-t/t mice (harboring non-functional truncated gravin) were started on blocker therapy. There was no significant reduction in the HW/BW ratio or the fibrotic lesions after Carvedilol and Bisoprolol treatment in the WT mice; whereas, gravin-t/t mice did not show any significant increase in either of the two after isoproterenol treatment. Gravin-t/t mice treated with either of these blockers showed enhanced hemodynamic function compared to the WT mice on the blocker therapy. Interestingly, the gravin-t/t mice after treatment with Carvedilol showed significant increase in the β2-AR expression (579.83 ± 0. 476 fmol/mg) compared to the WT mice (113.74 ± 0. 359 fmol/mg) treated with Carvedilol; whereas, no significant changes were observed in the β1-AR expression in WT (310.03 ± 0. 284 fmol/mg) or gravin-t/t mice (282.54 ± 0. 392 fmol/mg). Bisoprolol treatment on the other hand showed significant increase only in the β1-AR expression post treatment for both WT (405.62 ± 0. 264 fmol/mg) and gravin-t/t (421.01 ± 0. 382 fmol/mg) mice. Though Carvedilol is the gold standard for HF, and it increases the contractile function of the failing heart, it does not rescue the decline in the receptor density. Absence of gravin not only increases the β2-AR expression 2-fold at baseline but also increases it 5-fold after Carvedilol treatment. Disruption of gravin’s scaffolding is a potential drug target and can be further developed as a combination therapy with Carvedilol. Increase in β2-ARs expression can provide beneficial effects via activation of anti-apoptotic and survival pathways.