Simultaneous Adrenal and Cardiac G-Protein-Coupled Receptor-Gβγ Inhibition Halts Heart Failure Progression

Objectives The authors propose simultaneous inhibition of G beta gamma signaling in the heart and the adrenal gland as a novel therapeutic approach for heart failure (HF). Background Elevated sympathetic nervous system activity is a salient characteristic of HF progression. It causes pathologic desensitization of beta-adrenergic receptors (beta-AR), facilitated predominantly through G beta gamma-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal alpha(2)-AR feedback inhibitory function is impaired also through Gbg-mediated signaling. Methods We investigated the efficacy of a small molecule Gbg inhibitor, gallein, in a clinically relevant, pressure-overload model of HF. Results Daily gallein treatment (10 mg/kg/day), initiated 4 weeks after transverse aortic constriction, improved survival and cardiac function and attenuated cardiac remodeling. Mechanistically, gallein restored beta-AR membrane density in cardiomyocytes, attenuated Gbg-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase g membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3 beta phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal alpha(2)-AR feedback inhibition. In human adrenal endocrine tumors (pheochromocytoma), gallein attenuated catecholamine secretion, as well as G-protein-coupled receptor kinase 2 expression and membrane translocation. Conclusions These data suggest small molecule Gbg inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gbg signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gbg inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF. (C) 2014 by the American College of Cardiology Foundation