International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand

Pharmacological Reviews - Tập 71 Số 4 - Trang 467-502 - 2019
Cai Read1,2,3, Duuamene Nyimanu1,2,3, Thomas Williams1,2,3, David J. Huggins1,2,3, Petra Šulentić1,2,3, Robyn Macrae1,2,3, Peiran Yang1,2,3, Robert C. Glen1,2,3, Janet J. Maguire1,2,3, Anthony P. Davenport1,2,3
1Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, United Kingdom (R.C.G.)
2Experimental Medicine and Immunotherapeutics, University of Cambridge, Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, United Kingdom (C.R., D.N., T.L.W., D.J.H., P.S., R.G.C.M., P.Y., J.J.M., A.P.D.)
3The Centre for Molecular Informatics, Department of Chemistry, University of Cambridge, Cambridge, United Kingdom (D.J.H., R.C.G.)

Tóm tắt

Từ khóa


Tài liệu tham khảo

Aboouf, 2015, Genotype screening of APLN rs3115757 variant in Egyptian women population reveals an association with obesity and insulin resistance, Diabetes Res Clin Pract, 109, 40, 10.1016/j.diabres.2015.05.016

Akcılar, 2015, The effects of apelin treatment on a rat model of type 2 diabetes, Adv Med Sci, 60, 94, 10.1016/j.advms.2014.11.001

Akcılar, 2015, APJ receptor A445C gene polymorphism in Turkish patients with coronary artery disease, Int J Clin Exp Med, 8, 18793

Akcılar, 2015, Characterization of the apelin -1860T>C polymorphism in Turkish coronary artery disease patients and healthy individuals, Int J Physiol Pathophysiol Pharmacol, 7, 165

10.1172/JCI43382

10.1111/bph.13878

Alipour, 2017, An overview on biological functions and emerging therapeutic roles of apelin in diabetes mellitus, Diabetes Metab Syndr, 11, S919, 10.1016/j.dsx.2017.07.016

10.1016/j.rmed.2009.05.011

10.1016/j.cardiores.2004.08.018

10.2478/s11658-006-0058-7

10.2337/db11-0100

Balkau, 1999, Insulin resistance: an independent risk factor for cardiovascular disease?, Diabetes Obes Metab, 1, S23, 10.1046/j.1463-1326.1999.0010s1023.x

10.1161/CIRCHEARTFAILURE.111.000077

10.1007/978-1-61779-909-9_9

Berry, 2004, Apelin has in vivo inotropic effects on normal and failing hearts, Circulation, 110, II187

10.1172/JCI74773

Bertrand, 2015, Apelin and energy metabolism, Front Physiol, 6, 115, 10.3389/fphys.2015.00115

Blanc, 2015, SwissPalm: protein palmitoylation database, F1000Res, 4, 261, 10.12688/f1000research.6464.1

10.1038/srep16104

10.1210/en.2004-1427

10.1038/nrd3845

10.1016/S0304-3940(02)00411-1

10.1161/HYPERTENSIONAHA.114.05099

Brash, 2018, Short-term hemodynamic effects of apelin in patients with pulmonary arterial hypertension, JACC Basic Transl Sci, 3, 176, 10.1016/j.jacbts.2018.01.013

10.1074/jbc.M110.154526

10.1007/s12020-011-9507-9

10.1016/j.tem.2012.02.005

Castan-Laurell, 2019, The apelin/APJ system as a therapeutic target in metabolic diseases, Expert Opin Ther Targets, 23, 215, 10.1080/14728222.2019.1561871

10.1128/JVI.74.24.11972-11976.2000

10.1074/jbc.M113.541698

10.1161/ATVBAHA.110.219980

10.1016/j.ejheart.2008.06.002

Chapman, 2014, The apelin receptor: physiology, pathology, cell signalling, and ligand modulation of a peptide-activated class A GPCR, Biochem Cell Biol, 92, 431, 10.1139/bcb-2014-0072

10.1152/ajpheart.00686.2009

10.1016/j.ejphar.2015.05.017

Chen, 2015, Apelin protects against acute renal injury by inhibiting TGF-β1, Biochim Biophys Acta, 1852, 1278, 10.1016/j.bbadis.2015.02.013

10.1681/ASN.2016111210

10.1161/01.CIR.0000091235.94914.75

Chen N Chen X Chen Y Cheng AC Connors RV Deignan J Dransfield PJ Du X Fu Z Heath JA (2017b) Triazole agonists of the APJ receptor. Patent WO2016187308A1. 2016 May 18.

Chen, 2017, Association of apelin and apelin receptor with the risk of coronary artery disease: a meta-analysis of observational studies, Oncotarget, 8, 57345, 10.18632/oncotarget.17360

10.1074/jbc.M114.574020

Chen, 2016, Apelin/APJ system: a novel therapeutic target for myocardial ischemia/reperfusion injury, DNA Cell Biol, 35, 766, 10.1089/dna.2016.3391

Cheng, 2019, Apelin/APJ system: a potential therapeutic target for endothelial dysfunction-related diseases, J Cell Physiol, 234, 12149, 10.1002/jcp.27942

10.1016/j.devcel.2013.11.002

Choe, 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, 6113, 10.1128/JVI.72.7.6113-6118.1998

10.1016/j.ejheart.2005.10.007

Chun, 2008, Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis, J Clin Invest, 118, 3343

10.2174/157339909787314149

10.1016/j.cardfail.2015.03.007

Davenport, 2018, First in human study of a novel biased apelin receptor ligand, MM54, a G-alpha(i) agonist/beta-arrestin antagonist (Abstract), Circ Res, 123, E70

10.1124/pr.112.007179

10.1152/ajprenal.00306.2012

10.1159/000054609

10.1073/pnas.0403518101

10.1074/jbc.M115.648238

Deshwar, 2016, The apelin receptor enhances Nodal/TGFβ signaling to ensure proper cardiac development, eLife, 5, e13758, 10.7554/eLife.13758

10.1165/rcmb.2010-0412OC

10.1038/s41586-018-0236-6

10.1016/j.cmet.2008.10.003

10.1053/j.gastro.2013.01.004

Edinger, 1998, An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus, J Virol, 72, 7934, 10.1128/JVI.72.10.7934-7940.1998

10.1111/j.1471-4159.2004.02591.x

10.1046/j.1471-4159.2001.00269.x

10.1152/ajpheart.00089.2009

Falcone, 2012, APJ polymorphisms in coronary artery disease patients with and without hypertension, Mol Med Rep, 5, 321

10.1021/bi030049s

Fan, 2015, The apelin-APJ axis is an endogenous counterinjury mechanism in experimental acute lung injury, Chest, 147, 969, 10.1378/chest.14-1426

Fan, 2015, Treatment with metformin and a dipeptidyl peptidase-4 inhibitor elevates apelin levels in patients with type 2 diabetes mellitus, Drug Des Devel Ther, 9, 4679, 10.2147/DDDT.S85740

Flahault, 2017, Role of the vasopressin/apelin balance and potential use of metabolically stable apelin analogs in water metabolism disorders, Front Endocrinol (Lausanne), 8, 120, 10.3389/fendo.2017.00120

10.1111/j.1748-1716.2010.02175.x

10.1016/S0006-291X(03)01424-4

10.1136/gutjnl-2015-310230

10.1016/j.ejheart.2006.06.005

Freyer, 2017, Loss of apela peptide in mice causes low penetrance embryonic lethality and defects in early mesodermal derivatives, Cell Rep, 20, 2116, 10.1016/j.celrep.2017.08.014

10.1152/ajplung.00006.2015

10.2174/138161212799277770

10.1074/jbc.M116.748103

Ganguly, 2019, APELA expression in glioma, and its association with patient survival and tumor grade, Pharmaceuticals (Basel), 12, 1, 10.3390/ph12010045

10.1096/fj.14-256339

Gilbert, 2017, From apelin to exercise: emerging therapies for management of hypertension in pregnancy, Hypertens Res, 40, 519, 10.1038/hr.2017.40

10.1016/j.regpep.2005.09.032

Golosov A Grosche P Hu QY Imase H Parker DT Yasoshima K Zecri F Zhao H (2013) Synthetic apelin mimetics for the treatment of heart failure. Patent WO2013111110A3. 2013 Jan 25.

Gourdy, 2018, Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp, Diabetes Obes Metab, 20, 157, 10.1111/dom.13055

Guo, 2015, Apelin promotes diabetic nephropathy by inducing podocyte dysfunction via inhibiting proteasome activities, J Cell Mol Med, 19, 2273, 10.1111/jcmm.12619

10.3109/07435800903287079

Gupta, 2016, Biochemical and genetic role of apelin in essential hypertension and acute coronary syndrome, Int J Cardiol, 223, 374, 10.1016/j.ijcard.2016.07.242

Habata, 1999, Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum, Biochim Biophys Acta, 1452, 25, 10.1016/S0167-4889(99)00114-7

Hachtel S Wohlfart P Weston J Müller M Defossa E Mertsch K Weng J Binnie RA Abdul-Latif F Bock WJ (2014) Benzoimidazole-carboxylic acid amide derivatives as APJ receptor modulators. Patent WO2014044738A1. 2013 Sep 19.

10.1152/ajpheart.00703.2013

Hamada, 2008, Evaluation of novel cyclic analogues of apelin, Int J Mol Med, 22, 547

10.1210/en.2014-1631

10.1016/j.regpep.2007.02.002

Harford-Wright, 2017, Pharmacological targeting of apelin impairs glioblastoma growth, Brain, 140, 2939, 10.1093/brain/awx253

10.1016/j.gep.2010.02.001

Hata, 2011, Genome-wide association study for ischemic stroke based on the Hisayama study, Nihon Eiseigaku Zasshi, 66, 47, 10.1265/jjh.66.47

10.1093/hmg/ddm005

10.1016/j.yfrne.2011.07.002

Helker, 2015, The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis, eLife, 4, 6726, 10.7554/eLife.06726

Hinohara, 2009, Validation of the association between AGTRL1 polymorphism and coronary artery disease in the Japanese and Korean populations, J Hum Genet, 54, 554, 10.1038/jhg.2009.78

10.1016/j.stem.2015.08.010

10.1126/science.aam6607

10.1074/jbc.M908417199

Hu, 2016, Apelin/APJ system as a therapeutic target in diabetes and its complications, Mol Genet Metab, 119, 20, 10.1016/j.ymgme.2016.07.012

Huang, 2016, Associations between gene polymorphisms of the apelin-APJ system and the risk of hypertension, Blood Press, 25, 257, 10.3109/08037051.2016.1156905

Huang, 2016, The apelin-APJ axis: a novel potential therapeutic target for organ fibrosis, Clin Chim Acta, 456, 81, 10.1016/j.cca.2016.02.025

Huang, 2018, Apelin/APJ system: a novel potential therapy target for kidney disease, J Cell Physiol, 233, 3892, 10.1002/jcp.26144

10.1210/en.2014-1257

10.1038/ki.2008.199

Hutchings, 2017, Opportunities for therapeutic antibodies directed at G-protein-coupled receptors, Nat Rev Drug Discov, 16, 661, 10.1038/nrd.2017.173

10.1074/jbc.M404149200

10.1096/fj.09-140715

10.1074/jbc.M110.127167

10.1016/j.yjmcc.2006.07.004

10.1016/j.jacc.2008.06.013

10.1161/CIRCULATIONAHA.109.911339

Jia, 2015, Apelin polymorphism predicts blood pressure response to losartan in older Chinese women with essential hypertension, Genet Mol Res, 14, 6561, 10.4238/2015.June.12.10

10.1371/journal.pone.0051123

10.1016/j.regpep.2005.09.033

10.1016/j.peptides.2012.09.003

Juhl, 2016, Development of potent and metabolically stable APJ ligands with high therapeutic potential, ChemMedChem, 11, 2378, 10.1002/cmdc.201600307

10.1161/CIRCRESAHA.113.301324

10.1038/sj.bjp.0703939

Kawamata, 2001, Molecular properties of apelin: tissue distribution and receptor binding, Biochim Biophys Acta, 1538, 162, 10.1016/S0167-4889(00)00143-9

Khan P Maloney PR Hedrick M Gosalia P Milewski M Li L Roth GP Sergienko E Suyama E Sugarman E (2011) Functional agonists of the apelin (APJ) receptor. Probe Reports from the NIH Molecular Libraries Program, National Center for Biotechnology Information, Bethesda, MD.

10.1016/j.devcel.2015.02.024

10.1038/sj.emboj.7601982

10.14348/molcells.2014.2308

10.1016/j.regpep.2003.11.002

10.1016/j.pharmthera.2005.04.001

10.1016/j.regpep.2004.10.019

Kocer, 2016, Evaluation of fibrosis markers: apelin and transforming growth factor-β1 in autosomal dominant polycystic kidney disease patients, Ther Apher Dial, 20, 517, 10.1111/1744-9987.12412

10.1253/circj.CJ-11-0689

10.1172/JCI44824

Kotanidou, 2015, Apelin and G212A apelin receptor gene polymorphism in obese and diabese youth, Pediatr Obes, 10, 213, 10.1111/ijpo.251

10.1161/CIRCRESAHA.107.158659

Kuba, 2019, Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology, Peptides, 111, 62, 10.1016/j.peptides.2018.04.011

Kumar, 2016, Apelin binding to human APJ receptor leads to biased signaling, Biochim Biophys Acta, 1864, 1748, 10.1016/j.bbapap.2016.09.012

10.1093/nar/gkv353

10.1021/bi9830516

Langelaan, 2013, Structural features of the apelin receptor N-terminal tail and first transmembrane segment implicated in ligand binding and receptor trafficking, Biochim Biophys Acta, 1828, 1471, 10.1016/j.bbamem.2013.02.005

10.1096/fj.03-1273rev

10.1046/j.1471-4159.2000.0740034.x

10.1016/j.bbrc.2010.03.151

10.1210/en.2004-0359

10.1096/fj.201601074R

Li, 2016, A promoter polymorphism in APJ gene is significantly associated with blood pressure changes and hypertension risk in Chinese women, Oncotarget, 7, 86257, 10.18632/oncotarget.13370

10.1055/s-2006-948309

10.1152/ajpheart.00366.2012

10.1371/journal.pone.0071041

10.1016/j.stem.2015.04.002

10.1097/HJH.0b013e32832a3eb1

10.3945/ajcn.110.008813

10.1016/j.mce.2015.04.006

Lin, 2015, GSK2374697, a long duration glucagon-like peptide-1 (GLP-1) receptor agonist, reduces postprandial circulating endogenous total GLP-1 and peptide YY in healthy subjects, Diabetes Obes Metab, 17, 1007, 10.1111/dom.12533

Luo, 2018, Apelin/APJ system: a critical regulator of vascular smooth muscle cell, J Cell Physiol, 233, 5180, 10.1002/jcp.26339

Lv, 2017, Apelin/APJ system: a key therapeutic target for liver disease, Oncotarget, 8, 112145, 10.18632/oncotarget.22841

Ma, 2014, Plasma apelin: a novel biomarker for predicting diabetes, Clin Chim Acta, 435, 18, 10.1016/j.cca.2014.03.030

10.1016/j.str.2017.04.008

Macaluso, 2010, Exploring the ‘RPRL’ motif of apelin-13 through molecular simulation and biological evaluation of cyclic peptide analogues, ChemMedChem, 5, 1247, 10.1002/cmdc.201000061

10.1002/cmdc.201100069

10.1161/HYPERTENSIONAHA.109.134619

10.1016/j.bmcl.2012.08.105

Margathe, 2014, Structure-activity relationship studies toward the discovery of selective apelin receptor agonists, J Med Chem, 57, 2908, 10.1021/jm401789v

10.1006/bbrc.2001.6230

10.1074/jbc.M600606200

10.1016/S0304-3940(96)13198-0

McAnally, 2017, A systematic approach to identify biased agonists of the apelin receptor through high-throughput screening, SLAS Discov, 22, 867, 10.1177/2472555217699158

McKeown, 2014, The design and implementation of a generic lipopeptide scanning platform to enable the identification of ‘locally acting’ agonists for the apelin receptor, Bioorg Med Chem Lett, 24, 4871, 10.1016/j.bmcl.2014.08.045

McKinnie, 2016, The metalloprotease neprilysin degrades and inactivates apelin peptides, ChemBioChem, 17, 1495, 10.1002/cbic.201600244

10.1046/j.1471-4159.2003.01587.x

10.1021/pr200725x

10.1073/pnas.1422759112

10.3389/fphys.2017.00777

Murza, 2015, C-Terminal modifications of apelin-13 significantly change ligand binding, receptor signaling, and hypotensive action, J Med Chem, 58, 2431, 10.1021/jm501916k

10.1002/cmdc.201100492

Murza, 2016, Discovery and structure-activity relationship of a bioactive fragment of elabela that modulates vascular and cardiac functions, J Med Chem, 59, 2962, 10.1021/acs.jmedchem.5b01549

Murza, 2017, Structure-activity relationship of novel macrocyclic biased apelin receptor agonists, Org Biomol Chem, 15, 449, 10.1039/C6OB02247B

Myers MC Lawrence RM Bilder DM Meng W Pi Z Brigance RP Finlay H (2017) Heteroarylhydroxypyrimidinones as agonists of the APJ receptor. Patent WO2017106396A1. 2016 Dec 15.

10.1161/CIRCULATIONAHA.115.018174

Narayanan, 2016, Discovery of a novel small molecule agonist scaffold for the APJ receptor, Bioorg Med Chem, 24, 3758, 10.1016/j.bmc.2016.06.018

10.14814/phy2.13438

10.1164/rccm.201412-2291OC

10.1097/HJH.0b013e32833b1fad

10.1126/scisignal.2001707

Nyimanu, 2018, The apelin-36 mutant peptide N-58 (apelin 36-[l28A]) and its pegylated analogue N-140 (apelin 36-[L2c-30kDa-PEG) that mediate beneficial metabolic actions are G-protein biased ligands at the apelin receptor (Abstract), Circulation, 138, 15595

10.1046/j.1365-2826.2003.01044.x

10.1530/JOE-13-0227

O’Carroll, 2000, Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues, Biochim Biophys Acta, 1492, 72, 10.1016/S0167-4781(00)00072-5

10.1016/0378-1119(93)90495-O

O’Harte, 2018, Long-term treatment with acylated analogues of apelin-13 amide ameliorates diabetes and improves lipid profile of high-fat fed mice, PLoS One, 13, e0202350, 10.1371/journal.pone.0202350

O’Harte, 2018, Apelin-13 analogues show potent in vitro and in vivo insulinotropic and glucose lowering actions, Peptides, 100, 219, 10.1016/j.peptides.2017.12.004

Pakizeh, 2015, The assessment of the relationship between variations in the apelin gene and coronary artery disease in Turkish population, Anatol J Cardiol, 15, 716, 10.5152/akd.2014.5685

10.1093/nar/gkx1109

Pang, 2014, Effect of apelin on the cardiac hemodynamics in hypertensive rats with heart failure, Int J Mol Med, 34, 756, 10.3892/ijmm.2014.1829

10.1038/ncomms11268

10.1038/nature23477

10.1007/s10741-015-9515-6

10.1126/science.1248636

10.1002/bies.201400103

Perjés, 2016, Characterization of apela, a novel endogenous ligand of apelin receptor, in the adult heart, Basic Res Cardiol, 111, 2, 10.1007/s00395-015-0521-6

10.1371/journal.pone.0093473

Pinkerton AB Smith LH (2015) Agonists of the apelin receptor and methods of use thereof. Patent WO2015184011A2. 2015 May 27.

Pisarenko, 2015, Structural apelin analogues: mitochondrial ROS inhibition and cardiometabolic protection in myocardial ischaemia reperfusion injury, Br J Pharmacol, 172, 2933, 10.1111/bph.13038

Pisarenko, 2015, Signaling pathways of a structural analogue of apelin-12 involved in myocardial protection against ischemia/reperfusion injury, Peptides, 73, 67, 10.1016/j.peptides.2015.09.001

10.1124/pr.110.002949

10.1016/j.peptides.2011.12.005

Pope, 2016, Agonist-induced internalization and desensitization of the apelin receptor, Mol Cell Endocrinol, 437, 108, 10.1016/j.mce.2016.07.040

10.1002/hep.22467

10.1006/viro.2000.0557

10.1016/S0163-7258(02)00300-5

10.1016/j.bcp.2016.07.018

Read C Fitzpatrick CM Yang P Kuc RE Nyimanu D Maguire JJ Glen RC Foster R Davenport AP (2017) CMF-019, the first G protein biased small molecule apelin agonist, is a vasodilator and positive inotrope in vivo (Abstract), in APSA-ASCEPT 2017 Joint Scientific Meeting; 2017 December 5-8; Brisbane, Australia. pp 33, APSA-ASCEPT.

Read C Yang P Kuc RE Nyimanu D Williams TL Glen RC Holt LJ Arulanantham H Smart A Davenport AP (2019) Apelin peptides linked to anti-serum albumin domain antibodies retain affinity in vitro and are efficacious receptor agonists in vivo. Basic Clin Pharmacol Toxicol DOI: 1111/bcpt.13227 [published ahead of print].

10.1046/j.1471-4159.2001.00320.x

10.1016/S0306-4522(02)00192-6

10.1152/ajpendo.00521.2005

10.1210/en.2004-0384

10.1016/j.cell.2008.08.040

10.1124/jpet.111.188078

10.1093/protein/gzn039

10.1016/j.regpep.2010.03.005

10.1677/JOE-09-0134

10.1016/j.cardfail.2007.04.002

Sato, 2017, ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage, Cardiovasc Res, 113, 760, 10.1093/cvr/cvx061

Schreiber, 2017, Sustained ELABELA gene therapy in high-salt diet-induced hypertensive rats, Curr Gene Ther, 16, 349, 10.2174/1566523217666161121111906

10.1586/14779072.2014.911661

10.1038/nature11263

10.1016/j.devcel.2007.01.012

Serpooshan, 2015, [Pyr1]-Apelin-13 delivery via nano-liposomal encapsulation attenuates pressure overload-induced cardiac dysfunction, Biomaterials, 37, 289, 10.1016/j.biomaterials.2014.08.045

10.1016/j.devcel.2017.08.008

10.1016/j.fob.2013.08.001

10.1016/j.regpep.2005.05.004

10.1073/pnas.1508838112

Soualmia, 2017, The A445C variant in apelin receptor and diabetic retinopathy in Tunisian patients, Clin Lab, 63, 379, 10.7754/Clin.Lab.2016.160424

10.1177/1087057113475480

10.1172/JCI65592

10.1161/01.RES.0000033522.37861.69

10.1006/bbrc.2002.6575

10.1006/bbrc.1998.9489

10.1016/S0167-0115(01)00236-1

Thenappan, 2018, Role of extracellular matrix in the pathogenesis of pulmonary arterial hypertension, Am J Physiol Heart Circ Physiol, 315, H1322, 10.1152/ajpheart.00136.2018

10.1016/j.tips.2008.05.006

10.1210/en.2008-0178

Trifonov, 2018, An expedient synthesis of CMF-019: (S)-5-methyl-3-{1-(pentan-3-yl)-2- (thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxamido}hexanoic acid, a potent apelin receptor (APJ) agonist, Med Chem, 14, 688, 10.2174/1573406414666180412154952

Turecek, 2016, PEGylation of biopharmaceuticals: a review of chemistry and nonclinical safety information of approved drugs, J Pharm Sci, 105, 460, 10.1016/j.xphs.2015.11.015

10.1021/bi980497d

Velazquez, 2019, Angiotensin-neprilysin inhibition in acute decompensated heart failure, N Engl J Med, 380, 539, 10.1056/NEJMoa1812851

10.1074/jbc.M200581200

10.1038/s41591-018-0131-6

10.1164/rccm.200909-1361OC

10.1210/en.2003-1116

10.1016/j.regpep.2009.07.016

Wang, 2014, The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis, Amino Acids, 46, 2693, 10.1007/s00726-014-1826-8

Wang, 2013, Effects of acute intravenous infusion of apelin on left ventricular function in dogs with advanced heart failure, J Card Fail, 19, 509, 10.1016/j.cardfail.2013.05.004

Wang, 2015, Association of SNP Rs9943582 in APLNR with left ventricle systolic dysfunction in patients with coronary artery disease in a Chinese han GeneID population, PLoS One, 10, e0125926, 10.1371/journal.pone.0125926

10.1161/HYPERTENSIONAHA.115.06892

10.1161/JAHA.113.000249

Wang, 2015, Elabela-apelin receptor signaling pathway is functional in mammalian systems, Sci Rep, 5, 8170, 10.1038/srep08170

10.1016/j.peptides.2013.08.005

10.1038/s41580-018-0049-3

Wu, 2017, Apelin/APJ system: a novel promising therapy target for pathological angiogenesis, Clin Chim Acta, 466, 78, 10.1016/j.cca.2016.12.023

10.3389/fnmol.2017.00264

10.1093/abbs/gmu032

Yang, 2017, [Pyr1]apelin-13(1-12) is a biologically active ACE2 metabolite of the endogenous cardiovascular peptide [Pyr1]apelin-13, Front Neurosci, 11, 92, 10.3389/fnins.2017.00092

10.1016/j.tips.2015.06.002

10.1161/CIRCULATIONAHA.116.023218

Yang, 2019, A novel cyclic biased agonist of the apelin receptor, MM07, is disease modifying in the rat monocrotaline model of pulmonary arterial hypertension, Br J Pharmacol, 176, 1206, 10.1111/bph.14603

Yang, 2015, Apelin-13 protects the heart against ischemia-reperfusion injury through the RISK-GSK-3β-mPTP pathway, Arch Med Sci, 11, 1065

Yang, 2016, Apelin/APJ system and cancer, Clin Chim Acta, 457, 112, 10.1016/j.cca.2016.04.001

Yi, 2017, APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner, Gynecol Oncol, 147, 663, 10.1016/j.ygyno.2017.10.016

10.1152/ajpendo.00385.2009

Zhang, 2017, A Study of GWAS-supported variants of rs9943582 in a Chinese Han population with ischemic stroke: no associations with disease onset and clinical outcomes, J Stroke Cerebrovasc Dis, 26, 2294, 10.1016/j.jstrokecerebrovasdis.2017.05.013

Zhang, 2016, Apelin as a marker for monitoring the tumor vessel normalization window during antiangiogenic therapy, Cancer Sci, 107, 36, 10.1111/cas.12836

Zhang, 2009, Association of apelin genetic variants with type 2 diabetes and related clinical features in Chinese Hans, Chin Med J (Engl), 122, 1273

10.1016/j.bmc.2014.04.001

Zhang, 1998, Use of coreceptors other than CCR5 by non-syncytium-inducing adult and pediatric isolates of human immunodeficiency virus type 1 is rare in vitro, J Virol, 72, 9337, 10.1128/JVI.72.11.9337-9344.1998

10.1038/ajh.2010.36

10.1016/j.ab.2013.07.006

Zheng, 2016, The association between single nucleotide polymorphisms of the apelin gene and diabetes mellitus in a Chinese population, J Pediatr Endocrinol Metab, 29, 1397, 10.1515/jpem-2015-0441

10.1016/S0042-6822(02)00021-1

10.1016/S0042-6822(03)00185-5

Zhou, 2017, Effects of apelin on cardiovascular aging, Front Physiol, 8, 1035, 10.3389/fphys.2017.01035

Zhu, 2015, Apelin and APLN single nucleotide polymorphisms and combined hypertension and central retinal artery stenosis in a Chinese population, Clin Exp Hypertens, 37, 280, 10.3109/10641963.2014.960970

10.1016/S0014-5793(00)01487-3