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

Abstract

Objective We propose simultaneous inhibition of Gβ γ 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 as well as 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 Evolving Impact of G Protein-Coupled Receptor Kinases in Cardiac Health and Disease

“…Gallein actually targets G␤␥ binding and so is analogous to ␤-ARKct expression. Although other targets of G␤␥ binding were found, the primary mechanisms for heart failure reversal with gallein was G␤␥-GRK2 inhibition (122). Overall, evidence strongly supports the fact that inhibition of GRK2 in treating heart failure patients can be beneficial though ␤-ARKct gene therapy or emerging small molecules, and this will probably become a clinical reality in the near future.…”

“…Although paroxetine may not be an ideal candidate for heart failure therapy, currently it is a prototype molecule that can lead medicinal chemists to develop the first selective small molecule pharmacological GRK2 inhibitor. Of note, another compound gallein, which is not a candidate for a viable human drug, has been shown recently to reverse the CSQ transgenic mouse model of heart failure (122). Gallein actually targets G␤␥ binding and so is analogous to ␤-ARKct expression.…”

G-ProteinβγSubunit Dimers Modulate Kidney Repair after Ischemia-Reperfusion Injury in Rats

“…Although there is a lack of pharmacologic inhibitors targeting AGS proteins, Gbg dimer function can be manipulated in vivo through the use of small molecule inhibitors. For example, administration of gallein and M119 [2-(3,4,5-trihydroxy-6-oxoxanthen-9-yl)cyclohexane-1-carboxylic acid], the small molecule inhibitors of Gbg, has been shown to improve cardiac function and slow disease progression in mouse models of heart failure (Casey et al, 2010;Kamal et al, 2014). In contrast to the heart, the role of Gbg signaling in kidney injury remains poorly characterized.…”

Effect of High Thoracic Sympathetic Nerve Block on Serum Collagen Biomarkers in Patients with Chronic Heart Failure

“…We excluded patients with comorbidities, such as lung, liver, kidney, bone and metabolic disorders, as these potentially confound results and show that HTSB reduces myocardial fibrosis. It has been proven that inhibition of sympathetic excitation by different means blunts myocardial fibrosis in HF [8,9,10,11]. However, the effects of HTSB on myocardial fibrosis have not been revealed before.…”

“…It has been proven that inhibition of sympathetic excitation in HF blunts myocardial fibrosis [8,9,10,11]. Thoracic epidural anaesthesia inhibits thoracic sympathetic activity and provides cardiac protection during cardiac surgery [12,13].…”