Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression

Fadia A. Kamal, Deanne M. Mickelsen, Katherine M. Wegman, Joshua G. Travers, Jacob Moalem, Stephen R. Hammes, Alan V. Smrcka, Burns C. Blaxall

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Objectives The authors propose simultaneous inhibition of Gβγ 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 β-adrenergic receptors (β-AR), facilitated predominantly through Gβγ-mediated signaling. The adrenal glands are key contributors to the chronically elevated plasma catecholamine levels observed in HF, where adrenal α2-AR feedback inhibitory function is impaired also through Gβγ-mediated signaling. Methods We investigated the efficacy of a small molecule Gβγ 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 β-AR membrane density in cardiomyocytes, attenuated Gβγ-mediated G-protein-coupled receptor kinase 2-phosphoinositide 3-kinase γ membrane recruitment, and reduced Akt (protein kinase B) and glycogen synthase kinase 3β phosphorylation. Gallein also reduced circulating plasma catecholamine levels and catecholamine production in isolated mouse adrenal glands by restoring adrenal α2-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 Gβγ inhibition as a systemic pharmacologic therapy for HF by simultaneously normalizing pathologic adrenergic/Gβγ signaling in both the heart and the adrenal gland. Our data also suggest important endocrine/cardiovascular interactions and a possible role for small molecule Gβγ inhibition in treating endocrine tumors such as pheochromocytoma, in addition to HF.

Original languageEnglish (US)
Pages (from-to)2549-2557
Number of pages9
JournalJournal of the American College of Cardiology
Volume63
Issue number23
DOIs
StatePublished - Jun 17 2014

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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