The apelin receptor: Physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR

Biochemistry and Cell Biology

Volumn 92, Issue 6, 2014, Pages 431-440

  Chapman, Nigel A ^a   Dupré, Denis J ^a   Rainey, Jan K ^a,b  

^a DALHOUSIE UNIVERSITY   (Canada)

^b DALHOUSIE UNIVERSITY   (Canada)

Author keywords

Apelinergic system; APJ; APLNR; Peptide activated GPCR; Signal transduction

Indexed keywords

BACTERIOPHAGES; CELL SIGNALING; CHEMICAL ACTIVATION; DISEASES; LIGANDS; METABOLISM; MODULATION; PATHOLOGY; PEPTIDES; PHYSIOLOGY; PROTEINS; SIGNAL TRANSDUCTION;

APELINERGIC SYSTEM; APJ; APLNR; CARDIO-VASCULAR DISEASE; EMBRYONIC DEVELOPMENT; G PROTEIN COUPLED RECEPTORS; PHYSIOLOGICAL EFFECTS; THERAPEUTIC TARGETS;

BIOACTIVITY;

APELIN; APELIN RECEPTOR; G PROTEIN COUPLED RECEPTOR; HETERODIMER; ISOPROTEIN; LIGAND; PROTEIN ELABELA; UNCLASSIFIED DRUG; APLN PROTEIN, HUMAN; APLNR PROTEIN, HUMAN; SIGNAL PEPTIDE; TODDLER PEPTIDE, ZEBRAFISH; ZEBRAFISH PROTEIN;

ANGIOGENESIS; CARDIOVASCULAR DISEASE; DIABETES MELLITUS; EMBRYO DEVELOPMENT; ENERGY METABOLISM; FLUID BALANCE; HEART MUSCLE CONTRACTILITY; METABOLIC REGULATION; NEOPLASM; NONHUMAN; OBESITY; PATHOPHYSIOLOGY; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION; VASOCONSTRICTION; VASODILATATION; ZEBRA FISH; ANIMAL; ANIMAL EMBRYO; EMBRYOLOGY; GENETICS; HUMAN; METABOLISM; PATHOLOGY;

ANIMALS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS; EMBRYO, NONMAMMALIAN; EMBRYONIC DEVELOPMENT; HUMANS; INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS; NEOPLASMS; OBESITY; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION; ZEBRAFISH; ZEBRAFISH PROTEINS;

EID: 84911427828     PISSN: 08298211     EISSN: 12086002     Source Type: Journal    
DOI: 10.1139/bcb-2014-0072     Document Type: Review

References (78)

1. Ahmed S.M. Angers S. 2013. Emerging non-canonical functions for heterotrimeric G proteins in cellular signaling. J. Recept. Signal Transduct. Res. 33 (3): 177-183. 10.3109/10799893.2013.795972. 23721574.
2. Ahn S. Shenoy S.K. Wei H. Lefkowitz R.J. 2004. Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J. Biol. Chem. 279 (34): 35518-35525. 10.1074/jbc.M405878200. 15205453.
3. Ashley E.A. Powers J. Chen M. Kundu R. Finsterbach T. Caffarelli A. et al 2005. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc. Res. 65 (1): 73-82. 10.1016/j.cardiores.2004.08.018. 15621035.
4. Attane C. Foussal C. Le Gonidec S. Benani A. Daviaud D. Wanecq E. et al 2012. Apelin treatment increases complete Fatty Acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes, 61 (2): 310-320. 10.2337/db11-0100. 22210322.
5. Azizi M. Iturrioz X. Blanchard A. Peyrard S. De Mota N. Chartrel N. et al 2008. Reciprocal regulation of plasma apelin and vasopressin by osmotic stimuli. J. Am. Soc. Nephrol. 19 (5): 1015-1024. 10.1681/ASN.2007070816. 18272843.
6. Bai B. Liu L. Zhang N. Wang C. Jiang Y. Chen J. 2014. Heterodimerization of human apelin and bradykinin 1 receptors: novel signal transduction characteristics. Cell. Signal. 26 (7): 1549-1559. 10.1016/j.cellsig.2014.03.022. 24686079.
7. Blaukat A. Barac A. Cross M.J. Offermanns S. Dikic I. 2000. G protein-coupled receptor-mediated mitogen-activated protein kinase activation through cooperation of Galpha(q) and Galpha(i) signals. Mol. Cell. Biol. 20 (18): 6837-6848. 10.1128/MCB.20.18.6837-6848.2000. 10958680.
8. Boucher J. Masri B. Daviaud D. Gesta S. Guigne C. Mazzucotelli A. et al 2005. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology, 146 (4): 1764-1771. 10.1210/en.2004-1427. 15677759.
9. Brailoiu G.C. Dun S.L. Yang J. Ohsawa M. Chang J.K. Dun N.J. 2002. Apelin-immunoreactivity in the rat hypothalamus and pituitary. Neurosci. Lett. 327 (3): 193-197. 10.1016/S0304-3940(02)00411-1. 12113910.
10. Burch M.L. Getachew R. Osman N. Febbraio M.A. Little P.J. 2013. Thrombin-mediated proteoglycan synthesis utilizes both protein-tyrosine kinase and serine/threonine kinase receptor transactivation in vascular smooth muscle cells. J. Biol. Chem. 288 (10): 7410-7419. 10.1074/jbc.M112.400259. 23335513.
11. Castan-Laurell I. Dray C. Knauf C. Kunduzova O. Valet P. 2012. Apelin, a promising target for type 2 diabetes treatment? Trends Endocrinol. Metab. 23 (5): 234-241. 10.1016/j.tem.2012.02.005. 22445464.
12. Cayabyab M. Hinuma S. Farzan M. Choe H. Fukusumi S. Kitada C. et al 2000. Apelin, the natural ligand of the orphan seven-transmembrane receptor APJ, inhibits human immunodeficiency virus type 1 entry. J. Virol. 74 (24): 11972-11976. 10.1128/JVI.74.24.11972-11976.2000. 11090199.
13. Charles C.J. Rademaker M.T. Richards A.M. 2006. Apelin-13 induces a biphasic haemodynamic response and hormonal activation in normal conscious sheep. J. Endocrinol. 189 (3): 701-710. 10.1677/joe.1.06804. 16731800.
14. Chen H. Zheng C. Zhang X. Li J. Li J. Zheng L. Huang K. 2011. Apelin alleviates diabetes-associated endoplasmic reticulum stress in the pancreas of Akita mice. Peptides, 32 (8): 1634-1639. 10.1016/j.peptides.2011.06.025. 21762740.
15. Cheng X. Cheng X.S. Pang C.C. 2003. Venous dilator effect of apelin, an endogenous peptide ligand for the orphan APJ receptor, in conscious rats. Eur. J. Pharmacol. 470 (3): 171-175. 10.1016/S0014-2999(03)01821-1. 12798955.
16. Chng S.C. Ho L. Tian J. Reversade B. 2013. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev. Cell, 27 (6): 672-680. 10.1016/j.devcel.2013.11.002. 24316148.
17. Choe H. Farzan M. Konkel M. Martin K. Sun Y. Marcon L. et al 1998. The orphan seven-transmembrane receptor apj supports the entry of primary T-cell-line-tropic and dualtropic human immunodeficiency virus type 1. J. Virol. 72 (7): 6113-6118. 9621075.
18. Chun H.J. Ali Z.A. Kojima Y. Kundu R.K. Sheikh A.Y. Agrawal R. et al 2008. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J. Clin. Invest. 118 (10): 3343-3354. 10.1172/JCI34871. 18769630.
19. Clarke K.J. Whitaker K.W. Reyes T.M. 2009. Diminished metabolic responses to centrally-administered apelin-13 in diet-induced obese rats fed a high-fat diet. J. Neuroendocrinol. 21 (2): 83-89. 10.1111/j.1365-2826.2008.01815.x. 19076266.
20. Cox C.M. D'Agostino S.L. Miller M.K. Heimark R.L. Krieg P.A. 2006. Apelin, the ligand for the endothelial G-protein-coupled receptor, APJ, is a potent angiogenic factor required for normal vascular development of the frog embryo. Dev. Biol. 296 (1): 177-189. 10.1016/j.ydbio.2006.04.452. 16750822.
21. Dai L. Smith P.M. Kuksis M. Ferguson A.V. 2013. Apelin acts in the subfornical organ to influence neuronal excitability and cardiovascular function. J. Physiol. 591 (. Pt. 13): 3421-3432. 10.1113/jphysiol.2013.254144. 23629509.
22. De Mota N. Reaux-Le Goazigo A. El Messari S. Chartrel N. Roesch D. Dujardin C. et al 2004. Apelin, a potent diuretic neuropeptide counteracting vasopressin actions through inhibition of vasopressin neuron activity and vasopressin release. Proc. Natl. Acad. Sci. U.S.A. 101 (28): 10464-10469. 10.1073/pnas.0403518101. 15231996.
23. El Messari S. Iturrioz X. Fassot C. De Mota N. Roesch D. Llorens-Cortes C. 2004. Functional dissociation of apelin receptor signaling and endocytosis: implications for the effects of apelin on arterial blood pressure. J. Neurochem. 90 (6): 1290-1301. 10.1111/j.1471-4159.2004.02591.x. 15341513.
24. Evans N.A. Groarke D.A. Warrack J. Greenwood C.J. Dodgson K. Milligan G. Wilson S. 2001. Visualizing differences in ligand-induced beta-arrestin-GFP interactions and trafficking between three recently characterized G protein-coupled receptors. J. Neurochem. 77 (2): 476-485. 10.1046/j.1471-4159.2001.00269.x. 11299310.
25. Fleming I. Busse R. 2003. Molecular mechanisms involved in the regulation of the endothelial nitric oxide synthase. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284 (1): R1-R12. 10.1152/ajpregu.00323.2002. 12482742.
26. Heinonen M.V. Purhonen A.K. Miettinen P. Paakkonen M. Pirinen E. Alhava E. et al 2005. Apelin, orexin-A and leptin plasma levels in morbid obesity and effect of gastric banding. Regul. Pept. 130 (1-2): 7-13. 10.1016/j.regpep.2005.05.003. 15970339.
27. Kagiyama S. Fukuhara M. Matsumura K. Lin Y. Fujii K. Iida M. 2005. Central and peripheral cardiovascular actions of apelin in conscious rats. Regul. Pept. 125 (1-3): 55-59. 10.1016/j.regpep.2004.07.033. 15582714.
28. Kalin R.E. Kretz M.P. Meyer A.M. Kispert A. Heppner F.L. Brandli A.W. 2007. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev. Biol. 305 (2): 599-614. 10.1016/j.ydbio.2007.03.004. 17412318.
29. Kang Y. Kim J. Anderson J.P. Wu J. Gleim S.R. Kundu R.K. et al 2013. Apelin-APJ signaling is a critical regulator of endothelial MEF2 activation in cardiovascular development. Circ. Res. 113 (1): 22-31. 10.1161/CIRCRESAHA.113.301324. 23603510.
30. Kawamata Y. Habata Y. Fukusumi S. Hosoya M. Fujii R. Hinuma S. et al 2001. Molecular properties of apelin: tissue distribution and receptor binding. Biochim. Biophys. Acta, 1538 (2-3): 162-171. 10.1016/S0167-4889(00)00143-9. 11336787.
31. Kenakin T. 2011. Functional selectivity and biased receptor signaling. J. Pharmacol. Exp. Ther. 336 (2): 296-302. 10.1124/jpet.110.173948. 21030484.
32. Kleinz M.J. Davenport A.P. 2005. Emerging roles of apelin in biology and medicine. Pharmacol. Ther. 107 (2): 198-211. 10.1016/j.pharmthera.2005.04.001. 15907343.
33. Langelaan D.N. Rainey J.K. 2009. Headgroup-dependent membrane catalysis of apelin-receptor interactions is likely. J. Phys. Chem. B, 113 (30): 10465-10471. 10.1021/jp904562q. 19708686.
34. Langelaan D.N. Bebbington E.M. Reddy T. Rainey J.K. 2009. Structural insight into G-protein coupled receptor binding by apelin. Biochemistry, 48 (3): 537-548. 10.1021/bi801864b. 19123778.
35. Lee D.K. Cheng R. Nguyen T. Fan T. Kariyawasam A.P. Liu Y. et al 2000. Characterization of apelin, the ligand for the APJ receptor. J. Neurochem. 74 (1): 34-41. 10.1046/j.1471-4159.2000.0740034.x. 10617103.
36. Lee D.K. Saldivia V.R. Nguyen T. Cheng R. George S.R. O'Dowd B.F. 2005. Modification of the terminal residue of apelin-13 antagonizes its hypotensive action. Endocrinology, 146 (1): 231-236. 10.1210/en.2004-0359. 15486224.
37. Lee D.K. Ferguson S.S. George S.R. O'Dowd B.F. 2010. The fate of the internalized apelin receptor is determined by different isoforms of apelin mediating differential interaction with beta-arrestin. Biochem. Biophys. Res. Commun. 395 (2): 185-189. 10.1016/j.bbrc.2010.03.151. 20353754.
38. Li Y. Chen J. Bai B. Du H. Liu Y. Liu H. 2012. Heterodimerization of human apelin and kappa opioid receptors: roles in signal transduction. Cell Signal. 24 (5): 991-1001. 10.1016/j.cellsig.2011.12.012. 22200678.
39. Liebmann C. 2011. EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol. Cell. Endocrinol. 331 (2): 222-231. 10.1016/j.mce.2010.04.008. 20398727.
40. Luttrell L.M. Lefkowitz R.J. 2002. The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals. J. Cell Sci. 115 (. Pt. 3): 455-465. 11861753.
41. Macaluso N.J. Glen R.C. 2010. Exploring the 'RPRL' motif of apelin-13 through molecular simulation and biological evaluation of cyclic peptide analogues. ChemMedChem, 5 (8): 1247-1253. 10.1002/cmdc.201000061. 20486151.
42. Macaluso N.J. Pitkin S.L. Maguire J.J. Davenport A.P. Glen R.C. 2011. Discovery of a competitive apelin receptor (APJ) antagonist. ChemMedChem, 6 (6): 1017-1023. 10.1002/cmdc.201100069. 21560248.
43. Maguire J.J. Kleinz M.J. Pitkin S.L. Davenport A.P. 2009. [Pyr1]apelin-13 identified as the predominant apelin isoform in the human heart: vasoactive mechanisms and inotropic action in disease. Hypertension, 54 (3): 598-604. 10.1161/HYPERTENSIONAHA.109.134619. 19597036.
44. Masri B. Lahlou H. Mazarguil H. Knibiehler B. Audigier Y. 2002. Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein. Biochem. Biophys. Res. Commun. 290 (1): 539-545. 10.1006/bbrc.2001.6230. 11779205.
45. Masri B. Knibiehler B. Audigier Y. 2005. Apelin signalling: a promising pathway from cloning to pharmacology. Cell Signal. 17 (4): 415-426. 10.1016/j.cellsig.2004.09.018. 15601620.
46. Masri B. Morin N. Pedebernade L. Knibiehler B. Audigier Y. 2006. The apelin receptor is coupled to Gi1 or Gi2 protein and is differentially desensitized by apelin fragments. J. Biol. Chem. 281 (27): 18317-18326. 10.1074/jbc.M600606200. 16679320.
47. Mesmin C. Dubois M. Becher F. Fenaille F. Ezan E. 2010. Liquid chromatography/tandem mass spectrometry assay for the absolute quantification of the expected circulating apelin peptides in human plasma. Rapid Commun. Mass Spectrom. 24 (19): 2875-2884. 10.1002/rcm.4718. 20857448.
48. Mesmin C. Fenaille F. Becher F. Tabet J.C. Ezan E. 2011. Identification and characterization of apelin peptides in bovine colostrum and milk by liquid chromatography-mass spectrometry. J. Proteome Res. 10 (11): 5222-5231. 10.1021/pr200725x. 21939284.
49. Mukhin Y.V. Garnovsky E.A. Ullian M.E. Garnovskaya M.N. 2003. Bradykinin B2 receptor activates extracellular signal-regulated protein kinase in mIMCD-3 cells via epidermal growth factor receptor transactivation. J. Pharmacol. Exp. Ther. 304 (3): 968-977. 10.1124/jpet.102.043943. 12604671.
50. Murza A. Parent A. Besserer-Offroy E. Tremblay H. Karadereye F. Beaudet N. et al 2012. Elucidation of the structure-activity relationships of apelin: influence of unnatural amino acids on binding, signaling, and plasma stability. ChemMedChem, 7 (2): 318-325. 10.1002/cmdc.201100492. 22170700.
51. Neves S.R. Ram P.T. Iyengar R. 2002. G protein pathways. Science, 296 (5573): 1636-1639. 10.1126/science.1071550. 12040175.
52. Newson M.J. Pope G.R. Roberts E.M. Lolait S.J. O'Carroll A.M. 2013. Stress-dependent and gender-specific neuroregulatory roles of the apelin receptor in the hypothalamic-pituitary-adrenal axis response to acute stress. J. Endocrinol. 216 (1): 99-109. 10.1530/JOE-12-0375. 23086141.
53. O'Carroll A.M. Lolait S.J. Harris L.E. Pope G.R. 2013. The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. J. Endocrinol. 219 (1): R13-R35. 10.1530/JOE-13-0227. 23943882.
54. O'Dowd B.F. Heiber M. Chan A. Heng H.H. Tsui L.C. Kennedy J.L. et al 1993. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene, 136 (1-2): 355-360. 10.1016/0378-1119(93)90495-O. 8294032.
55. Pauli A. Norris M.L. Valen E. Chew G.L. Gagnon J.A. Zimmerman S. et al 2014. Toddler: an embryonic signal that promotes cell movement via Apelin receptors. Science, 343 (6172): 1248636. 10.1126/science.1248636. 24407481.
56. Piairo P. Moura R.S. Nogueira-Silva C. Correia-Pinto J. 2011. The apelinergic system in the developing lung: expression and signaling. Peptides, 32 (12): 2474-2483. 10.1016/j.peptides.2011.10.010. 22015267.
57. Picault F.X. Chaves-Almagro C. Projetti F. Prats H. Masri B. Audigier Y. 2014. Tumour co-expression of apelin and its receptor is the basis of an autocrine loop involved in the growth of colon adenocarcinomas. Eur. J. Cancer, 50 (3): 663-674. 10.1016/j.ejca.2013.11.017. 24316062.
58. Pitkin S.L. Maguire J.J. Bonner T.I. Davenport A.P. 2010. International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol. Rev. 62 (3): 331-342. 10.1124/pr.110.002949. 20605969.
59. Reaux A. De Mota N. Skultetyova I. Lenkei Z. El Messari S. Gallatz K. et al 2001. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J. Neurochem. 77 (4): 1085-1096. 10.1046/j.1471-4159.2001.00320.x. 11359874.
60. Reaux A. Gallatz K. Palkovits M. Llorens-Cortes C. 2002. Distribution of apelin-synthesizing neurons in the adult rat brain. Neuroscience, 113 (3): 653-662. 10.1016/S0306-4522(02)00192-6. 12150785.
61. Roberts E.M. Pope G.R. Newson M.J. Landgraf R. Lolait S.J. O'Carroll A.M. 2010. Stimulus-specific neuroendocrine responses to osmotic challenges in apelin receptor knockout mice. J. Neuroendocrinol. 22 (4): 301-308. 10.1111/j.1365-2826.2010.01968.x. 20136689.
62. Scimia M.C. Hurtado C. Ray S. Metzler S. Wei K. Wang J. et al 2012. APJ acts as a dual receptor in cardiac hypertrophy. Nature, 488 (7411): 394-398. 10.1038/nature11263. 22810587.
63. Shin K. Pandey A. Liu X.Q. Anini Y. Rainey J.K. 2013. Preferential apelin-13 production by the proprotein convertase PCSK3 is implicated in obesity. FEBS Open Bio. 3: 328-333. 10.1016/j.fob.2013.08.001. 24251091.
64. Siddiquee K. Hampton J. McAnally D. May L. Smith L. 2013. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br. J. Pharmacol. 168 (5): 1104-1117. 10.1111/j.1476-5381.2012.02192.x. 22935142.
65. Sorhede Winzell M. Magnusson C. Ahren B. 2005. The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice. Regul. Pept. 131 (1-3): 12-17. 10.1016/j.regpep.2005.05.004. 15970338.
66. Szokodi I. Tavi P. Foldes G. Voutilainen-Myllyla S. Ilves M. Tokola H. et al 2002. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ. Res. 91 (5): 434-440. 10.1161/01.RES.0000033522.37861.69. 12215493.
67. Taheri S. Murphy K. Cohen M. Sujkovic E. Kennedy A. Dhillo W. et al 2002. The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats. Biochem. Biophys. Res. Commun. 291 (5): 1208-1212. 10.1006/bbrc.2002.6575. 11883945.
68. Tatemoto K. Hosoya M. Habata Y. Fujii R. Kakegawa T. Zou M.X. et al 1998. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun. 251 (2): 471-476. 10.1006/bbrc.1998.9489. 9792798.
69. Tatemoto K. Takayama K. Zou M.X. Kumaki I. Zhang W. Kumano K. Fujimiya M. 2001. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul. Pept. 99 (2-3): 87-92. 10.1016/S0167-0115(01)00236-1. 11384769.
70. Wang W. McKinnie S.M. Patel V.B. Haddad G. Wang Z. Zhabyeyev P. et al 2013. Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues. J. Am. Heart Assoc. 2 (4): e000249. 10.1161/JAHA.113.000249. 23817469.
71. Wei L. Hou X. Tatemoto K. 2005. Regulation of apelin mRNA expression by insulin and glucocorticoids in mouse 3T3-L1 adipocytes. Regul. Pept. 132 (1-3): 27-32. 10.1016/j.regpep.2005.08.003. 16137778.
72. Wertman J. Dupre D.J. 2013. G protein-coupled receptor dimers: look like their parents, but act like teenagers! J. Recept. Signal Transduct Res. 33 (3): 135-138. 10.3109/10799893.2012.759591. 23323734.
73. Yue P. Jin H. Aillaud M. Deng A.C. Azuma J. Asagami T. et al 2010. Apelin is necessary for the maintenance of insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 298 (1): E59-E67. 10.1152/ajpendo.00385.2009. 19861585.
74. Zhang Q. Yao F. Raizada M.K. O'Rourke S.T. Sun C. 2009 a. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ. Res. 104 (12): 1421-1428. 10.1161/CIRCRESAHA.108.192302. 19443838.
75. Zhang Z. Yu B. Tao G.Z. 2009 b. Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chin. Med. J. (Engl.), 122 (19): 2360-2365. 20079140.
76. Zhen E.Y. Higgs R.E. Gutierrez J.A. 2013. Pyroglutamyl apelin-13 identified as the major apelin isoform in human plasma. Anal. Biochem. 442 (1): 1-9. 10.1016/j.ab.2013.07.006. 23872001.
77. Zhou N. Fan X. Mukhtar M. Fang J. Patel C.A. DuBois G.C. Pomerantz R.J. 2003. Cell-cell fusion and internalization of the CNS-based, HIV-1 co-receptor, APJ. Virology, 307 (1): 22-36. 10.1016/S0042-6822(02)00021-1. 12667811.
78. Zou M.X. Liu H.Y. Haraguchi Y. Soda Y. Tatemoto K. Hoshino H. 2000. Apelin peptides block the entry of human immunodeficiency virus (HIV). FEBS Lett. 473 (1): 15-18. 10.1016/S0014-5793(00)01487-3. 10802050.