Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist

Hypertension

Volumn 65, Issue 4, 2015, Pages 834-840

  Brame, Aimee L ^a   Maguire, Janet J ^a   Yang, Peiran ^a   Dyson, Alex ^b   Torella, Rubben ^a   Cheriyan, Joseph ^a   Singer, Mervyn ^b   Glen, Robert C ^a   Wilkinson, Ian B ^a   Davenport, Anthony P ^a  

^a UNIVERSITY OF CAMBRIDGE   (United Kingdom)

^b UNIVERSITY COLLEGE LONDON   (United Kingdom)

Author keywords

pulmonary arterial hypertension; Pyr1 apelin 13; arrestin G protein coupled receptors

Indexed keywords

APELIN; APELIN RECEPTOR; APELIN RECEPTOR AGONIST; BETA ARRESTIN; CYCLOPEPTIDE; G PROTEIN COUPLED RECEPTOR; GUANINE NUCLEOTIDE BINDING PROTEIN; MM 07; UNCLASSIFIED DRUG; VASODILATOR AGENT; [PYR1 ]APELIN 13; ANTIPYRETIC AGENT; APELIN 13, PYR(1)-; APLNR PROTEIN, RAT; SIGNAL PEPTIDE;

AGONIST; ANIMAL EXPERIMENT; ARTICLE; CONTRACTION ASSAY; CONTROLLED STUDY; DRUG ANALYSIS; DRUG CONFORMATION; DRUG DESIGN; DRUG HALF LIFE; DRUG RECEPTOR BINDING; FIRST IN HUMAN STUDY; FOREARM BLOOD FLOW; HEART OUTPUT; HUMAN; HUMAN EXPERIMENT; HUMAN TISSUE; INOTROPISM; MALE; MOLECULAR DYNAMICS; NONHUMAN; NORMAL HUMAN; PRIORITY JOURNAL; RAT; RECEPTOR DOWN REGULATION; SAPHENOUS VEIN; SYSTEMIC VASCULAR RESISTANCE; VASODILATATION; VEIN OCCLUSION PLETHYSMOGRAPHY; AGONISTS; ANIMAL; DISEASE MODEL; DRUG EFFECTS; HYPERTENSION, PULMONARY; METABOLISM; METHODOLOGY; PATHOPHYSIOLOGY; WISTAR RAT;

ANIMALS; ANTIPYRETICS; DISEASE MODELS, ANIMAL; GTP-BINDING PROTEINS; HUMANS; HYPERTENSION, PULMONARY; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; MALE; RATS; RATS, WISTAR; RECEPTORS, G-PROTEIN-COUPLED; RESEARCH DESIGN; SAPHENOUS VEIN; VASODILATION;

EID: 84937596909     PISSN: 0194911X     EISSN: 15244563     Source Type: Journal    
DOI: 10.1161/HYPERTENSIONAHA.114.05099     Document Type: Article

References (46)

1. Tatemoto K, Hosoya M, Habata Y, Fujii R, Kakegawa T, Zou MX, Kawamata Y, Fukusumi S, Hinuma S, Kitada C, Kurokawa T, Onda H, Fujino M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem Biophys Res Commun. 1998; 251: 471-476. doi: 10.1006/bbrc.1998.9489
2. Japp AG, Cruden NL, Amer DA, Li VK, Goudie EB, Johnston NR, Sharma S, Neilson I, Webb DJ, Megson IL, Flapan AD, Newby DE. Vascular effects of apelin in vivo in man. J Am Coll Cardiol. 2008; 52: 908-913. doi: 10.1016/j.jacc.2008.06.013
3. Maguire JJ, Kleinz MJ, Pitkin SL, Davenport AP. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension. 2009; 54: 598-604. doi: 10.1161/HYPERTENSIONAHA.109.134619
4. Salcedo A, Garijo J, Monge L, Fernández N, Luis García-Villalón A, Sánchez Turrión V, Cuervas-Mons V, Diéguez G. Apelin effects in human splanchnic arteries. Role of nitric oxide and prostanoids. Regul Pept. 2007; 144: 50-55. doi: 10.1016/j.regpep.2007.06.005
5. Pitkin SL, Maguire JJ, Bonner TI, Davenport AP. International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol Rev. 2010; 62: 331-342. doi: 10.1124/pr.110.002949
6. Földes G, Horkay F, Szokodi I, Vuolteenaho O, Ilves M, Lindstedt KA, Mäyränpää M, Sármán B, Seres L, Skoumal R, Lakó-Futó Z, deChâtel R, Ruskoaho H, Tóth M. Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem Biophys Res Commun. 2003; 308: 480-485
7. Chong KS, Gardner RS, Morton JJ, Ashley EA, McDonagh TA. Plasma concentrations of the novel peptide apelin are decreased in patients with chronic heart failure. Eur J Heart Fail. 2006; 8: 355-360. doi: 10.1016/j. ejheart.2005.10.007
8. Chandrasekaran B, Kalra PR, Donovan J, Hooper J, Clague JR, McDonagh TA. Myocardial apelin production is reduced in humans with left ventricular systolic dysfunction. J Card Fail. 2010; 16: 556-561. doi: 10.1016/j. cardfail.2010.02.004
9. Pitkin SL, Maguire JJ, Kuc RE, Davenport AP. Modulation of the apelin/APJ system in heart failure and atherosclerosis in man. Br J Pharmacol. 2010; 160: 1785-1795. doi: 10.1111/j.1476-5381.2010.00821.x
10. Alastalo TP, Li M, Perez Vde J, Pham D, Sawada H, Wang JK, Koskenvuo M, Wang L, Freeman BA, Chang HY, Rabinovitch M. Disruption of PPARγ/β-catenin-mediated regulation of apelin impairs BMP-induced mouse and human pulmonary arterial EC survival. J Clin Invest. 2011; 121: 3735-3746. doi: 10.1172/JCI43382
11. Kim J, Kang Y, Kojima Y, Lighthouse JK, Hu X, Aldred MA, McLean DL, Park H, Comhair SA, Greif DM, Erzurum SC, Chun HJ. An endothelial apelin-FGF link mediated by miR-424 and miR-503 is disrupted in pulmonary arterial hypertension. Nat Med. 2013; 19: 74-82. doi: 10.1038/nm.3040
12. Chandra SM, Razavi H, Kim J, Agrawal R, Kundu RK, De Jesus Perez V, Zamanian RT, Quertermous T, Chun HJ. Disruption of the apelin-APJ system worsens hypoxia-induced pulmonary hypertension. Arterioscler Thromb Vasc Biol. 2011; 31: 814-820. doi: 10.1161/ATVBAHA.110.219980
13. Falcão-Pires I, Gonçalves N, Henriques-Coelho T, Moreira-Gonçalves D, Roncon-Albuquerque R Jr, Leite-Moreira AF. Apelin decreases myocardial injury and improves right ventricular function in monocrotalineinduced pulmonary hypertension. Am J Physiol Heart Circ Physiol. 2009; 296: H2007-H2014. doi: 10.1152/ajpheart.00089.2009
14. Evans NA, Groarke DA, Warrack J, Greenwood CJ, Dodgson K, Milligan G, Wilson S. Visualizing differences in ligand-induced beta-arrestin-GFP interactions and trafficking between three recently characterized G protein-coupled receptors. J Neurochem. 2001; 77: 476-485
15. Reaux A, De Mota N, Skultetyova I, Lenkei Z, El Messari S, Gallatz K, Corvol P, Palkovits M, Llorens-Cortès C. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem. 2001; 77: 1085-1096
16. Zhou N, Fan X, Mukhtar M, Fang J, Patel CA, DuBois GC, Pomerantz RJ. Cell-cell fusion and internalization of the CNS-based, HIV-1 co-receptor, APJ. Virology. 2003; 307: 22-36
17. Masri B, Morin N, Pedebernade L, Knibiehler B, Audigier Y. The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J Biol Chem. 2006; 281: 18317-18326. doi: 10.1074/jbc.M600606200
18. Scimia MC, Hurtado C, Ray S, et al. APJ acts as a dual receptor in cardiac hypertrophy. Nature. 2012; 488: 394-398. doi: 10.1038/nature11263
19. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD. A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013; 344: 708-717. doi: 10.1124/jpet.112.201616
20. Monasky MM, Taglieri DM, Henze M, Warren CM, Utter MS, Soergel DG, Violin JD, Solaro RJ. The β-arrestin-biased ligand TRV120023 inhibits angiotensin II-induced cardiac hypertrophy while preserving enhanced myofilament response to calcium. Am J Physiol Heart Circ Physiol. 2013; 305: H856-H866. doi: 10.1152/ajpheart.00327.2013
21. Kenakin T, Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nat Rev Drug Discov. 2013; 12: 205-216. doi: 10.1038/nrd3954
22. Medhurst AD, Jennings CA, Robbins MJ, Davis RP, Ellis C, Winborn KY, Lawrie KW, Hervieu G, Riley G, Bolaky JE, Herrity NC, Murdock P, Darker JG. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J Neurochem. 2003; 84: 1162-1172
23. Langelaan DN, Bebbington EM, Reddy T, Rainey JK. Structural insight into G-protein coupled receptor binding by apelin. Biochemistry. 2009; 48: 537-548. doi: 10.1021/bi801864b
24. Langelaan DN, Rainey JK. Headgroup-dependent membrane catalysis of apelin-receptor interactions is likely. J Phys Chem B. 2009; 113: 10465-10471. doi: 10.1021/jp904562q
25. SYBYL 7.3. St. Louis, MO: Tripos Inc.; 2006
26. Case DA, Pearlman DA, Caldwell JW, et al. AMBER, Version 7.San Francisco, CA: University of California; 2002
27. Berendsen HJC, van der Spoel D, van Drunen R. GROMACS: A messagepassing parallel molecular-dynamics implementation. Comp Phys Comm. 1995; 91: 43-56
28. Lindahl E, Hess B, van der Spoel D. GROMACS 3.0: a package for molecular simulation and trajectory analysis. J Mol Mod. 2001; 7: 306-317
29. Macaluso NJ, Pitkin SL, Maguire JJ, Davenport AP, Glen RC. Discovery of a competitive apelin receptor (APJ) antagonist. ChemMedChem. 2011; 6: 1017-1023. doi: 10.1002/cmdc.201100069
30. Sugita Y, Okamoto Y. Replica-exchange molecular dynamics method for protein folding. Chem Phys Lett. 1999; 314: 141-151
31. van der Westhuizen ET, Breton B, Christopoulos A, Bouvier M. Quantification of ligand bias for clinically relevant β2-adrenergic receptor ligands: implications for drug taxonomy. Mol Pharmacol. 2014; 85: 492-509. doi: 10.1124/mol.113.088880
32. Dyson A, Stidwill R, Taylor V, Singer M. Tissue oxygen monitoring in rodent models of shock. Am J Physiol Heart Circ Physiol. 2007; 293: H526-H533. doi: 10.1152/ajpheart.00052.2007
33. Japp AG, Cruden NL, Barnes G, van Gemeren N, Mathews J, Adamson J, Johnston NR, Denvir MA, Megson IL, Flapan AD, Newby DE. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation. 2010; 121: 1818-1827. doi: 10.1161/CIRCULATIONAHA.109.911339
34. Rabelo ER, Rohde LE, Schaan BD, Rubira MC, Ruschel KB, Plentz RD, Consolim-Colombo FM, Irigoyen MC, Moreno Junior H. Bradykinin or acetylcholine as vasodilators to test endothelial venous function in healthy subjects. Clinics (Sao Paulo). 2008; 63: 677-682
35. Sogo N, Wilkinson IB, MacCallum H, Khan SQ, Strachan FE, Newby DE, Megson IL, Webb DJ. A novel S-nitrosothiol (RIG200) causes prolonged relaxation in dorsal hand veins with damaged endothelium. Clin Pharmacol Ther. 2000; 68: 75-81. doi: 10.1067/mcp.2000.107049
36. Szokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysä J, Tóth M, Ruskoaho H. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002; 91: 434-440
37. Ashley EA, Powers J, Chen M, Kundu R, Finsterbach T, Caffarelli A, Deng A, Eichhorn J, Mahajan R, Agrawal R, Greve J, Robbins R, Patterson AJ, Bernstein D, Quertermous T. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res. 2005; 65: 73-82. doi: 10.1016/j.cardiores.2004.08.018
38. Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, Woo YJ. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation. 2004; 110(11 Suppl 1): II187-II193. doi: 10.1161/01. CIR.0000138382.57325.5c
39. Jia YX, Pan CS, Zhang J, Geng B, Zhao J, Gerns H, Yang J, Chang JK, Tang CS, Qi YF. Apelin protects myocardial injury induced by isoproterenol in rats. Regul Pept. 2006; 133: 147-154. doi: 10.1016/j.regpep.2005.09.033
40. Barnes GD, Alam S, Carter G, Pedersen CM, Lee KM, Hubbard TJ, Veitch S, Jeong H, White A, Cruden NL, Huson L, Japp AG, Newby DE. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013; 6: 482-491. doi: 10.1161/CIRCHEARTFAILURE.111.000077
41. Drexler H, Höing S, Faude F, Wollschläger H, Just H. Central and regional vascular hemodynamics following intravenous milrinone in the conscious rat: comparison with dobutamine. J Cardiovasc Pharmacol. 1987; 9: 563-569
42. Gardiner SM, Compton AM, Kemp PA, Bennett T, Hughes B, Foulkes R. Differential effects of (+/-)-dobutamine and human alpha-CGRP on cardiac and on regional haemodynamics in conscious Long Evans rats. Br J Pharmacol. 1991; 103: 1500-1508
43. Stephens J, Ead H, Spurrell R. Haemodynamic effects of dobutamine with special reference to myocardial blood flow. A comparison with dopamine and isoprenaline. Br Heart J. 1979; 42: 43-50
44. Perj?s α, Skoumal R, Tenhunen O, Ksnyi A, Simon M, Horvαth IG, Kerkeld R, Ruskoaho H, Szokodi I. Apelin increases cardiac contractility via protein kinase Cε-and extracellular signal-regulated kinasedependent mechanisms. PLoS One. 2014; 9: e93473. doi: 10.1371/journal. pone.0093473
45. Morrell NW, Adnot S, Archer SL, Dupuis J, Jones PL, MacLean MR, McMurtry IF, Stenmark KR, Thistlethwaite PA, Weissmann N, Yuan JX, Weir EK. Cellular and molecular basis of pulmonary arterial hypertension. J Am Coll Cardiol. 2009; 54(1 Suppl): S20-S31. doi: 10.1016/j. jacc.2009.04.018
46. Scimia MC, Blass BE, Koch WJ. Apelin receptor: its responsiveness to stretch mechanisms and its potential for cardiovascular therapy. Expert Rev Cardiovasc Ther. 2014; 12: 733-741. doi: 10.1586/14779072.2014.911661