Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression.
OBJECTIVE
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.
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Fadia A
FA
Kamal
Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester Medical Center, Rochester, New York.
Deanne M
DM
Mickelsen
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Katherine M
KM
Wegman
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
Joshua G
JG
Travers
Department of Surgery, University of Rochester Medical Center, Rochester, New York; Department of Medicine, University of Rochester Medical Center, Rochester, New York.
Jacob
J
Moalem
Department of Medicine, University of Rochester Medical Center, Rochester, New York.
Stephen R
SR
Hammes
Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York.
Alan V
AV
Smrcka
The Heart Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio. Electronic address: burns.blaxall@cchmc.org.
Burns C
BC
Blaxall
D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors*; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D013318:Stroke Volume; D016896:Treatment Outcome; D014966:Xanthenes / Q000008:administration & dosage / Q000627:therapeutic use*
D014966:Xanthenes; C007820:gallein; D054769:G-Protein-Coupled Receptor Kinase 2
catecholamines; fibrosis; heart failure; hypertrophy; sympathetic nervous system