Future G protein-coupled receptor targets for treatment of heart failure

  • Giuseppe Rengo
  • Anastasios Lymperopoulos
  • Walter J. Koch
Article

Opinion statement

Heart failure (HF) still poses an enormous clinical challenge, as its incidence, morbidity, and mortality rates are continuously rising. G protein-coupled receptors (GPCRs) constitute the most ubiquitous superfamily of plasma membrane receptors and represent the single most important type of therapeutic drug target. Because there is overstimulation of the failing heart by various endogenous ligands, such as catecholamines and angiotensin II—which by activating their cognate GPCRs in cardiac muscle induce detrimental effects—therapeutic targeting of these receptors has been pursued. This research has led to the development of successful and useful drug classes, such as angiotensin-converting enzyme inhibitors and β-adrenergic receptor blockers. However, there still is a need to develop innovative treatments that might be more effective at reversing compromised myocyte function. Over the past several years, much evidence has accumulated indicating that a single GPCR, activated by the same endogenous ligand, can elicit several different signaling pathways with quite different, and often opposite, cellular effects. Because the aforementioned ligands, currently used for HF, target these receptors on their extracellular interface, thus merely preventing the endogenous agonists from binding the receptor, they inhibit all the signaling pathways elicited by the receptor indiscriminately. Importantly, several of these pathways emanating from the same GPCR can actually be beneficial for therapy, so their enhancement rather than their blockade is desirable for HF therapy. This highlights the need for selective targeting of GPCR-induced signaling pathways on the intracellular interface of the receptor, which might produce new and innovative therapies for cardiovascular disease.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Pierce KL, Premont RT, Lefkowitz RJ: Seven-transmembrane receptors. Nat Rev Mol Cell Biol 2002, 3:639–650.PubMedCrossRefGoogle Scholar
  2. 2.
    Adorisio R, DeLuca L, Rossi J, Gheorghiade M: Pharmacological treatment of chronic heart failure. Heart Fail Rev 2006, 11:109–123.PubMedCrossRefGoogle Scholar
  3. 3.
    Bylund DB, Eikenberg DC, Hieble JP, et al.: International Union of Pharmacology nomenclature of adrenoceptors. Pharmacol Rev 1994, 46:121–136.PubMedGoogle Scholar
  4. 4.
    Rockman HA, Koch WJ, Lefkowitz RJ: Seven-transmembrane-spanning receptors and heart function. Nature 2002, 415:206–212.PubMedCrossRefGoogle Scholar
  5. 5.
    Cohn JN, Levine TB, Olivari MT, et al.: Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984, 311:819–823.PubMedGoogle Scholar
  6. 6.
    Dohlman HG, Thorner J, Caron MG, Lefkowitz RJ: Model systems for the study of seven-transmembrane-segment receptors. Annu Rev Biochem 1991, 60:653–688.PubMedCrossRefGoogle Scholar
  7. 7.
    Bristow MR: b-Adrenergic receptor blockade in chronic HF. Circulation 2000, 101:558–569.PubMedGoogle Scholar
  8. 8.
    Communal C, Singh K, Sawyer DB, Colucci WS: Opposing effects of b1- and b2-adrenergic receptors on cardiac myocyte apoptosis: role of a pertussis toxin-sensitive G protein. Circulation 1999, 100:2210–2212.PubMedGoogle Scholar
  9. 9.
    Zhu WZ, Zheng M, Koch WJ, et al.: Dual modulation of cell survival and cell death by b2-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001, 98:1607–1612.PubMedCrossRefGoogle Scholar
  10. 10.
    Liggett SB, Tepe NM, Lorenz JN, et al.: Early and delayed consequences of b2-adrenergic receptor overexpression in mouse hearts: critical role for expression level. Circulation 2000, 101:1707–1714.PubMedGoogle Scholar
  11. 11.
    Engelhardt S, Hein L, Wiesmann F, Lohse MJ: Progressive hypertrophy and heart failure in b1-adrenergic receptor transgenic mice. Proc Natl Acad Sci U S A 1999, 96:7059–7064.PubMedCrossRefGoogle Scholar
  12. 12.
    Ahmet I, Krawczyk M, Heller P, et al.: Beneficial effects of chronic pharmacological manipulation of b-adrenoreceptor subtype signaling in rodent dilated ischemic cardiomyopathy. Circulation 2004, 110:1083–1090.PubMedCrossRefGoogle Scholar
  13. 13.
    Maurice JP, Hata JA, Shah AS, et al.: Enhancement of cardiac function after adenoviral-mediated in vivo intra-coronary b2-adrenergic receptor gene delivery. J Clin Invest 1999, 104:21–29.PubMedCrossRefGoogle Scholar
  14. 14.
    DeGeorge BR Jr, Gao E, Boucher M, et al.: Targeted inhibition of cardiomyocyte Gi signaling enhances susceptibility to apoptotic cell death in response to ischemic stress. Circulation 2008, 117:1378–1387.PubMedCrossRefGoogle Scholar
  15. 15.
    Petrofski JA, Koch WJ: The b-adrenergic receptor kinase (bARK1) in heart failure. J Mol Cell Cardiol 2003, 35:1167–1174.PubMedCrossRefGoogle Scholar
  16. 16.
    Lefkowitz RJ, Shenoy SK: Transduction of receptor signals by b-arrestins. Science 2005, 308:512–517.PubMedCrossRefGoogle Scholar
  17. 17.
    Vinge LE, Raake PW, Koch WJ: Gene therapy in heart failure. Circ Res 2008, 102:1458–1470.PubMedCrossRefGoogle Scholar
  18. 18.
    Koch WJ, Inglese J, Stone WC, Lefkowitz RJ: The binding site for the bg subunits of heterotrimeric G proteins on the beta-adrenergic receptor kinase. J Biol Chem 1993, 268:8256–8260.PubMedGoogle Scholar
  19. 19.
    Koch WJ, Rockman HA, Samama P, et al.: Cardiac function in mice overexpressing the b-adrenergic receptor kinase or a bARK inhibitor. Science 1995, 268:1350–1353.PubMedCrossRefGoogle Scholar
  20. 20.
    Shah AS, White DC, Emani S, et al.: In vivo ventricular gene delivery of a b-adrenergic receptor kinase inhibitor to the failing heart reverses cardiac dysfunction. Circulation 2001, 103:1311–1316.PubMedCrossRefGoogle Scholar
  21. 21.
    White DC, Hata JA, Shah AS, et al.: Preservation of myocardial b-adrenergic receptor delays the development of heart failure following myocardial infarction. Proc Natl Acad Sci U S A 2000, 97:5428–5433.PubMedCrossRefGoogle Scholar
  22. 22.
    Williams ML, Hata JA, Schroder J, et al.: Targeted b-adrenergic receptor kinase (bARK1) inhibition by gene transfer in failing human hearts. Circulation 2004, 109:1590–1593.PubMedCrossRefGoogle Scholar
  23. 23.
    Rengo G, Lymperopoulos A, Zincarelli C, et al.: Myocardial adeno-associated virus serotype 6-bARKct gene therapy improves cardiac function and normalizes the neurohormonal axis in chronic heart failure. Circulation 2009, 119:89–98.PubMedCrossRefGoogle Scholar
  24. 24.
    Rockman HA, Choi DJ, Akhter SA, et al.: Control of myocardial contractile function by the level of beta-adrenergic receptor kinase 1 in gene-targeted mice. J Biol Chem 1998, 273:18180–18184.PubMedCrossRefGoogle Scholar
  25. 25.
    Raake PW, Vinge LE, Gao E, et al.: G protein-coupled receptor kinase 2 ablation in cardiac myocytes before or after myocardial infarction prevents heart failure. Circ Res 2008, 103:413–422.PubMedCrossRefGoogle Scholar
  26. 26.
    Dzimiri N, Muiya P, Andres E, Al-Halees Z: Differential functional expression of human myocardial G protein receptor kinases in left ventricular cardiac diseases. Eur J Pharmacol 2004, 489:167–177.PubMedCrossRefGoogle Scholar
  27. 27.
    Eckhart AD, Duncan SJ, Penn RB, et al.: Hybrid transgenic mice reveal in vivo specificity of G protein-coupled receptor kinases in the heart. Circ Res 2000, 86:43–50.PubMedGoogle Scholar
  28. 28.
    Liggett SB, Cresci S, Kelly RJ, et al.: A GRK5 polymorphism that inhibits beta-adrenergic receptor signaling is protective in heart failure. Nat Med 2008, 14:510–517.PubMedCrossRefGoogle Scholar
  29. 29.
    Noma T, Lemaire A, Naga Prasad SV, et al.: Beta-arrestin-mediated beta1-adrenergic receptor transactivation of the EGFR confers cardioprotection. J Clin Invest 2007, 117:2396–2398.CrossRefGoogle Scholar
  30. 30.
    Martini JS, Raake P, Vinge LE, et al.: Uncovering G protein-coupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes. Proc Natl Acad Sci U S A 2008, 105:12457–12462.PubMedCrossRefGoogle Scholar
  31. 31.
    Rajagopal K, Whalen EJ, Violin JD et al.: b-Arrestin2-mediated inotropic effects of the angiotensin II type 1A receptor in isolated cardiac myocytes. Proc Natl Acad Sci U S A 2006, 103:16284–16289.PubMedCrossRefGoogle Scholar
  32. 32.
    Richter W, Day P, Agrawal R, et al.: Signaling from beta1- and beta2-adrenergic receptors is defined by differential interactions with PDE4. EMBO J 2008, 27:384–393.PubMedCrossRefGoogle Scholar
  33. 33.
    Brede M, Nagy G, Philipp M, et al.: Differential control of adrenal and sympathetic catecholamine release by alpha 2-adrenoceptor subtypes. Mol Endocrinol 2003, 17:1640–1646.PubMedCrossRefGoogle Scholar
  34. 34.
    Lymperopoulos A, Rengo G, Funakoshi H, et al.: Adrenal GRK2 upregulation mediates sympathetic overdrive in heart failure. Nat Med 2007, 13:315–323.PubMedCrossRefGoogle Scholar
  35. 35.
    Lymperopoulos A, Rengo G, Zincarelli C, et al.: Modulation of adrenal catecholamine secretion by in vivo gene transfer and manipulation of G protein-coupled receptor kinase-2 activity. Mol Ther 2008, 16:302–307.PubMedCrossRefGoogle Scholar
  36. 36.
    Willenbrock R, Philipp S, Mitrovic V, Dietz R: Neurohumoral blockade in CHF management. J Renin Angiotensin Aldosterone Syst 2000, 1(Suppl 1):24–30.PubMedCrossRefGoogle Scholar
  37. 37.
    Berk BC: Angiotensin type 2 receptor (AT2R): a challenging twin. Sci STKE 2003, 181:PE16.Google Scholar
  38. 38.
    Matsumoto T, Wada A, Tsutamoto T, et al.: Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure. Circulation 2003, 107:2555–2558.PubMedCrossRefGoogle Scholar
  39. 39.
    Pfeffer MA, McMurray JJV, Velazquez EJ, et al.: Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003, 349:1893–1906.PubMedCrossRefGoogle Scholar
  40. 40.
    Cruden NL, Witherow FN, Webb DJ, et al.: Bradykinin contributes to the systemic hemodynamic effects of chronic angiotensin-converting enzyme inhibition in patients with heart failure. Arterioscler Thromb Vasc Biol 2004, 24:1043–1048.PubMedCrossRefGoogle Scholar
  41. 41.
    Violin JD, Lefkowitz RJ: Beta-arrestin-biased ligands at seven-transmembrane receptors. Trends Pharmacol Sci 2007, 28:416–422.PubMedCrossRefGoogle Scholar
  42. 42.
    Modlinger PS, Welch WJ: Adenosine A1 receptor antagonists and the kidney. Curr Opin Nephrol Hypertens 2003, 12:497–502.PubMedCrossRefGoogle Scholar
  43. 43.
    Gottlieb SS, Brater DC, Thomas I, et al.: BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002, 105:1348–1353.PubMedCrossRefGoogle Scholar
  44. 44.
    Headrick JP, Willems L, Ashton KJ, et al.: Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression. J Physiol 2003, 549:823–833.PubMedCrossRefGoogle Scholar
  45. 45.
    Liao Y, Takashima S, Asano Y, et al.: Activation of adenosine A1 receptor attenuates cardiac hypertrophy and prevents heart failure in murine left ventricular pressure-overload model. Circ Res 2003, 93:759–766.PubMedCrossRefGoogle Scholar
  46. 46.
    Funakoshi H, Chan TO, Good JC, et al.: Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function. Circulation 2006, 114:2240–2250.PubMedCrossRefGoogle Scholar
  47. 47.
    Chan TO, Funakosji H, Song K, et al.: Cardiac-restricted overexpression of the A2A-adenosine receptor in FVB mice transiently increases contractile performance and rescues the heart failure phenotype in mice overexpressing the A1-adenosine receptor. Clin Trans Sci 2008, 1:126–133.CrossRefGoogle Scholar
  48. 48.
    Kirkby NS, Hadoke PWF, Bagnall AJ, Webb DJ: The endothelin system as therapeutic target in cardiovascular disease: great expectations or bleak house? Br J Pharmacol 2008, 153:1105–1119.PubMedCrossRefGoogle Scholar
  49. 49.
    D’Orléans-Juste P, Labonté J, Bkaily G, et al.: Function of the endothelin(B) receptor in cardiovascular physiology and pathophysiology. Pharmacol Ther 2002, 221–238.Google Scholar

Copyright information

© Current Medicine Group, LLC 2009

Authors and Affiliations

  • Giuseppe Rengo
  • Anastasios Lymperopoulos
  • Walter J. Koch
    • 1
  1. 1.Center for Translational MedicineThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations