Abstract 1268: Small Molecule Targeting Of gβγ Reduces β-adrenergic Receptor Desensitization And Normalizes Cardiac Dysfunction In An Acute Heart Failure Model

Abstract

Heart failure (HF) is a debilitating disease with poor prognosis, despite substantial therapeutic advances in the past two decades. Excess signaling through cardiac G-protein Gβγ subunits is an important component of HF pathophysiology. They recruit elevated levels of cytosolic G-protein coupled receptor kinase 2 (GRK2, a.k.a. βARK1) to agonist-stimulated β-ARs in HF, leading to chronic β-AR desensitization and down-regulation; these events are all hallmarks of HF. Previous data has suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. We recently developed a novel small molecule targeting strategy to selectively inhibit Gβγ binding interactions, and identified several Gβγ inhibitory small molecules (Bonacci et al, Science, 2006). In particular, we identified compound M119, which blocked the interaction of purified Gβγ and GRK2 in vitro. To validate this activity in a cellular setting, we isolated adult mouse cardiomyocytes, where M119 significantly reduced β-AR-mediated membrane recruitment of GRK2. Furthermore, M119 significantly enhanced both adenylyl cyclase activity and cardiomyocyte contractility at baseline and in response to β-AR agonist stimulation. Upon finding that the compound was biologically available following intraperitoneal injection in mice, we investigated whether the observed in vitro effects in isolated adult cardiomyocytes would translate to in vivo effects on cardiac function. Initial investigations were pursued in an acute pharmacologic HF model (30 mg/kg/day isoproterenol for seven days). Importantly, concurrent once daily injections of M119 normalized cardiac function, morphology and GRK2 expression in this acute HF model. Collectively, our study has identified a small molecule Gβγ inhibitor capable of reducing β-AR desensitization, thereby enhancing β-AR-mediated isolated cardiomyocyte contractility and, importantly, normalizing cardiac function and morphology in an acute HF model in vivo. Our data suggest a promising therapeutic role for small molecule inhibition of Gβγ in the treatment of HF.