Small Molecule Disruption of Gβγ Signaling Inhibits the Progression of Heart Failure

Rationale: Excess signaling through cardiac G beta gamma subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein-coupled receptor kinase (GRK) 2 to agonist-stimulated beta-adrenergic receptors (beta-ARs) in HF, leading to chronic beta-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting G beta gamma signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule G beta gamma inhibition in HF. Methods and Results: We recently described novel small molecule G beta gamma inhibitors that selectively block G beta gamma-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of G beta gamma and GRK2 in vitro and in HL60 cells. Here, we show they reduced beta-AR-mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to beta-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and beta-myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological G beta gamma signaling in the treatment of HF. (Circ Res. 2010; 107: 532-539.)