Simultaneous Adrenal and Cardiac G-protein-coupled Receptor-gβγ Inhibition Halts Heart Failure Progression

Overview

Journal J Am Coll Cardiol

Specialty Cardiology & Vascular Diseases

Date 2014 Apr 8

PMID 24703913

Citations 29

Authors

Fadia A Kamal

Deanne M Mickelsen

Katherine M Wegman

Joshua G Travers

Jacob Moalem

Stephen R Hammes

Alan V Smrcka

Burns C Blaxall

Affiliations

Soon will be listed here.

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.

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References

Williams M, Hata J, Schroder J, Rampersaud E, Petrofski J, Jakoi A . Targeted beta-adrenergic receptor kinase (betaARK1) inhibition by gene transfer in failing human hearts. Circulation. 2004; 109(13):1590-3. DOI: 10.1161/01.CIR.0000125521.40985.28. View

Brede M, Nagy G, Philipp M, Sorensen J, Lohse M, Hein L . Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol. 2003; 17(8):1640-6. DOI: 10.1210/me.2003-0035. View

Rockman H, Chien K, Choi D, Iaccarino G, Hunter J, ROSS Jr J . Expression of a beta-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice. Proc Natl Acad Sci U S A. 1998; 95(12):7000-5. PMC: 22717. DOI: 10.1073/pnas.95.12.7000. View

Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M . PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell. 2004; 118(3):375-87. DOI: 10.1016/j.cell.2004.07.017. View

Naga Prasad S, Esposito G, Mao L, Koch W, Rockman H . Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem. 2000; 275(7):4693-8. DOI: 10.1074/jbc.275.7.4693. View

Nienaber J, Tachibana H, Naga Prasad S, Esposito G, Wu D, Mao L . Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest. 2003; 112(7):1067-79. PMC: 198526. DOI: 10.1172/JCI18213. View

Koch W, Lefkowitz R, Rockman H . Functional consequences of altering myocardial adrenergic receptor signaling. Annu Rev Physiol. 2000; 62:237-60. DOI: 10.1146/annurev.physiol.62.1.237. View

Harding V, Jones L, Lefkowitz R, Koch W, Rockman H . Cardiac beta ARK1 inhibition prolongs survival and augments beta blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A. 2001; 98(10):5809-14. PMC: 33295. DOI: 10.1073/pnas.091102398. View

Naga Prasad S, Jayatilleke A, Madamanchi A, Rockman H . Protein kinase activity of phosphoinositide 3-kinase regulates beta-adrenergic receptor endocytosis. Nat Cell Biol. 2005; 7(8):785-96. DOI: 10.1038/ncb1278. View

10.

Neumeister A, Charney D, Belfer I, Geraci M, Holmes C, Sharabi Y . Sympathoneural and adrenomedullary functional effects of alpha2C-adrenoreceptor gene polymorphism in healthy humans. Pharmacogenet Genomics. 2005; 15(3):143-9. DOI: 10.1097/01213011-200503000-00002. View

11.

Sussman M, Volkers M, Fischer K, Bailey B, Cottage C, Din S . Myocardial AKT: the omnipresent nexus. Physiol Rev. 2011; 91(3):1023-70. PMC: 3674828. DOI: 10.1152/physrev.00024.2010. View

12.

Naga Prasad S, Laporte S, Chamberlain D, Caron M, Barak L, Rockman H . Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol. 2002; 158(3):563-75. PMC: 2173831. DOI: 10.1083/jcb.200202113. View

13.

Bonacci T, Mathews J, Yuan C, Lehmann D, Malik S, Wu D . Differential targeting of Gbetagamma-subunit signaling with small molecules. Science. 2006; 312(5772):443-6. DOI: 10.1126/science.1120378. View

14.

Blaxall B, Spang R, Rockman H, Koch W . Differential myocardial gene expression in the development and rescue of murine heart failure. Physiol Genomics. 2003; 15(2):105-14. DOI: 10.1152/physiolgenomics.00087.2003. View

15.

Nagai T, Anzai T, Kaneko H, Mano Y, Anzai A, Maekawa Y . C-reactive protein overexpression exacerbates pressure overload-induced cardiac remodeling through enhanced inflammatory response. Hypertension. 2011; 57(2):208-15. DOI: 10.1161/HYPERTENSIONAHA.110.158915. View

16.

Oudit G, Sun H, Kerfant B, A Crackower M, Penninger J, Backx P . The role of phosphoinositide-3 kinase and PTEN in cardiovascular physiology and disease. J Mol Cell Cardiol. 2004; 37(2):449-71. DOI: 10.1016/j.yjmcc.2004.05.015. View

17.

Small K, McGraw D, Liggett S . Pharmacology and physiology of human adrenergic receptor polymorphisms. Annu Rev Pharmacol Toxicol. 2003; 43:381-411. DOI: 10.1146/annurev.pharmtox.43.100901.135823. View

18.

Lymperopoulos A, Rengo G, Funakoshi H, Eckhart A, Koch W . Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med. 2007; 13(3):315-23. DOI: 10.1038/nm1553. View

19.

Naga Prasad S, Barak L, Rapacciuolo A, Caron M, Rockman H . Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. J Biol Chem. 2001; 276(22):18953-9. DOI: 10.1074/jbc.M102376200. View

20.

Bristow M, Ginsburg R, Minobe W, Cubicciotti R, Sageman W, Lurie K . Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982; 307(4):205-11. DOI: 10.1056/NEJM198207223070401. View