apelin

Apelin is a peptide hormone that was identified in 1998 by Masahiko Fujino and his colleagues at Gunma University and Takeda Pharmaceutical Company. In 2013, a second peptide hormone named Elabela was found by Bruno Reversade to also act as an endogenous ligand to the APLNR.

The apelin gene encodes a pre-proprotein of 77 amino acids, with a signal peptide in the N-terminal region. After translocation into the endoplasmic reticulum and cleavage of the signal peptide, the proprotein of 55 amino acids may generate several active fragments: a 36 amino acid peptide corresponding to the sequence 42-77 (apelin 36), a 17 amino acid peptide corresponding to the sequence 61-77 (apelin 17) and a 13 amino acid peptide corresponding to the sequence 65-77 (apelin 13). This latter fragment may also undergo a pyroglutamylation at the level of its N-terminal glutamine residue. However the presence and/or the concentrations of those peptides in human plasma has been questioned.{{cite journal | vauthors = Mesmin C, Dubois M, Becher F, Fenaille F, Ezan E | title = Liquid chromatography/tandem mass spectrometry assay for the absolute quantification of the expected circulating apelin peptides in human plasma | journal = Rapid Communications in Mass Spectrometry | volume = 24 | issue = 19 | pages = 2875–2884 | date = October 2010 | pmid = 20857448 | doi = 10.1002/rcm.4718 | bibcode = 2010RCMS...24.2875M }} Recently, 46 different apelin peptides ranging from apelin 55 ({{not a typo|proapelin}}) to apelin 12 have been identified in bovine colostrum, including C-ter truncated isoforms.{{cite journal | vauthors = Mesmin C, Fenaille F, Becher F, Tabet JC, Ezan E | title = Identification and characterization of apelin peptides in bovine colostrum and milk by liquid chromatography-mass spectrometry | journal = Journal of Proteome Research | volume = 10 | issue = 11 | pages = 5222–5231 | date = November 2011 | pmid = 21939284 | doi = 10.1021/pr200725x }}

The sites of receptor expression are linked to the different functions played by apelin in the organism.

Vascular expression of the receptor{{cite journal | vauthors = Devic E, Rizzoti K, Bodin S, Knibiehler B, Audigier Y | title = Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ | journal = Mechanisms of Development | volume = 84 | issue = 1-2 | pages = 199–203 | date = June 1999 | pmid = 10473142 | doi = 10.1016/S0925-4773(99)00081-7 | s2cid = 14753955 | doi-access = free }}{{cite journal | vauthors = Saint-Geniez M, Masri B, Malecaze F, Knibiehler B, Audigier Y | title = Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels | journal = Mechanisms of Development | volume = 110 | issue = 1-2 | pages = 183–186 | date = January 2002 | pmid = 11744380 | doi = 10.1016/S0925-4773(01)00558-5 | s2cid = 16855047 | doi-access = free }} participates in the control of blood pressure and its activation promotes the formation of new blood vessels (angiogenesis).{{cite journal | vauthors = Masri B, Morin N, Cornu M, Knibiehler B, Audigier Y | title = Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells | journal = FASEB Journal | volume = 18 | issue = 15 | pages = 1909–1911 | date = December 2004 | pmid = 15385434 | doi = 10.1096/fj.04-1930fje | s2cid = 2013710 | doi-access = free }}{{cite journal | vauthors = Kasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, Hinuma S, Baba A | title = Apelin is a novel angiogenic factor in retinal endothelial cells | journal = Biochemical and Biophysical Research Communications | volume = 325 | issue = 2 | pages = 395–400 | date = December 2004 | pmid = 15530405 | doi = 10.1016/j.bbrc.2004.10.042 }}{{cite journal | vauthors = Cox CM, D'Agostino SL, Miller MK, Heimark RL, Krieg PA | title = 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 | journal = Developmental Biology | volume = 296 | issue = 1 | pages = 177–189 | date = August 2006 | pmid = 16750822 | doi = 10.1016/j.ydbio.2006.04.452 | doi-access = free }} The blood pressure-lowering (hypotensive) effect of apelin results from the activation of receptors expressed at the surface of endothelial cells. This activation induces the release of nitric oxide (NO),{{cite journal | vauthors = Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M | title = The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism | journal = Regulatory Peptides | volume = 99 | issue = 2-3 | pages = 87–92 | date = June 2001 | pmid = 11384769 | doi = 10.1016/S0167-0115(01)00236-1 | s2cid = 3064032 }} a potent vasodilator, which induces relaxation of the smooth muscle cells of artery wall. Studies performed on mice knocked out for the apelin receptor gene{{cite journal | vauthors = Ishida J, Hashimoto T, Hashimoto Y, Nishiwaki S, Iguchi T, Harada S, Sugaya T, Matsuzaki H, Yamamoto R, Shiota N, Okunishi H, Kihara M, Umemura S, Sugiyama F, Yagami K, Kasuya Y, Mochizuki N, Fukamizu A | title = Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo | journal = The Journal of Biological Chemistry | volume = 279 | issue = 25 | pages = 26274–26279 | date = June 2004 | pmid = 15087458 | doi = 10.1074/jbc.M404149200 | doi-access = free }} have suggested the existence of a balance between angiotensin II signalling (which increases blood pressure)e and apelin signalling (which lowers it). The angiogenic activity is the consequence of apelin action on the proliferation and migration of the endothelial cells. Apelin activates signal transduction cascades inside the cell, including extracellular signal-regulated kinases (ERKs), protein kinase B (PKB, also known as Akt), and p70 s6 kinase phosphorylation,{{cite journal | vauthors = Masri B, Lahlou H, Mazarguil H, Knibiehler B, Audigier Y | title = Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein | journal = Biochemical and Biophysical Research Communications | volume = 290 | issue = 1 | pages = 539–545 | date = January 2002 | pmid = 11779205 | doi = 10.1006/bbrc.2001.6230 }} which lead to the proliferation of endothelial cells and the formation of new blood vessels. Genetic knockout of the apelin gene is associated with a delay in the development of the retinal vasculature.{{cite journal | vauthors = Kasai A, Shintani N, Kato H, Matsuda S, Gomi F, Haba R, Hashimoto H, Kakuda M, Tano Y, Baba A | title = Retardation of retinal vascular development in apelin-deficient mice | journal = Arteriosclerosis, Thrombosis, and Vascular Biology | volume = 28 | issue = 10 | pages = 1717–1722 | date = October 2008 | pmid = 18599802 | doi = 10.1161/ATVBAHA.108.163402 | doi-access = free }}

The apelin receptor is expressed early during the embryonic development of the heart, where it regulates the migration of cell progenitors fated to differentiate into cardiomyocytes, the contractile cells of the heart.{{cite journal | vauthors = Scott IC, Masri B, D'Amico LA, Jin SW, Jungblut B, Wehman AM, Baier H, Audigier Y, Stainier DY | title = The g protein-coupled receptor agtrl1b regulates early development of myocardial progenitors | journal = Developmental Cell | volume = 12 | issue = 3 | pages = 403–413 | date = March 2007 | pmid = 17336906 | doi = 10.1016/j.devcel.2007.01.012 | doi-access = free }}{{cite journal | vauthors = Zeng XX, Wilm TP, Sepich DS, Solnica-Krezel L | title = Apelin and its receptor control heart field formation during zebrafish gastrulation | journal = Developmental Cell | volume = 12 | issue = 3 | pages = 391–402 | date = March 2007 | pmid = 17336905 | doi = 10.1016/j.devcel.2007.01.011 | doi-access = free }} Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.{{cite journal | vauthors = Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, Woo YJ | title = Apelin has in vivo inotropic effects on normal and failing hearts | journal = Circulation | volume = 110 | issue = 11 Suppl 1 | pages = II187-II193 | date = September 2004 | pmid = 15364861 | doi = 10.1161/01.CIR.0000138382.57325.5c | doi-access = free }}{{cite journal | vauthors = 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 | title = The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo | journal = Cardiovascular Research | volume = 65 | issue = 1 | pages = 73–82 | date = January 2005 | pmid = 15621035 | pmc = 2517138 | doi = 10.1016/j.cardiores.2004.08.018 }} Aged apelin knockout mice develop progressive impairment of cardiac contractility.{{cite journal | vauthors = Kuba K, Zhang L, Imai Y, Arab S, Chen M, Maekawa Y, Leschnik M, Leibbrandt A, Markovic M, Schwaighofer J, Beetz N, Musialek R, Neely GG, Komnenovic V, Kolm U, Metzler B, Ricci R, Hara H, Meixner A, Nghiem M, Chen X, Dawood F, Wong KM, Sarao R, Cukerman E, Kimura A, Hein L, Thalhammer J, Liu PP, Penninger JM | title = Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload | journal = Circulation Research | volume = 101 | issue = 4 | pages = e32-e42 | date = August 2007 | pmid = 17673668 | doi = 10.1161/CIRCRESAHA.107.158659 | doi-access = free }} Apelin acts as a mediator of the cardiovascular control, including for blood pressure and blood flow. It is one of the most potent stimulators of cardiac contractility yet identified, and plays a role in cardiac tissue remodeling. Apelin levels are increased in left ventricles of patients with chronic heart failure and also in patients with chronic liver disease.{{cite journal | vauthors = Principe A, Melgar-Lesmes P, Fernández-Varo G, del Arbol LR, Ros J, Morales-Ruiz M, Bernardi M, Arroyo V, Jiménez W | title = The hepatic apelin system: a new therapeutic target for liver disease | journal = Hepatology | volume = 48 | issue = 4 | pages = 1193–1201 | date = October 2008 | pmid = 18816630 | doi = 10.1002/hep.22467 | doi-access = free }}

The plasma concentration of apelin is shown to increase during exercise.{{cite journal |vauthors=Kechyn S, Barnes G, Howard L| title = Assessing dynamic changes in plasma apelin concentration in response to maximal exercise in man | journal = European Respiratory Journal |year=2015 |volume=46 |page=PA2316 | doi = 10.1183/13993003.congress-2015.PA2316}} Paradoxically, exogenous apelin in healthy volunteers reduced VO2 peak (peak oxygen consumption) in an endurance test.{{cite journal | vauthors = Kechyn S, Barnes G, Thongmee A, Howard LS |title=Effect of apelin on cardiopulmonary performance during endurance exercise |journal=European Respiratory Journal |date=September 2015 |volume=46 |issue=suppl 59 |pages=2241 |doi=10.1183/13993003.congress-2015.PA2241}}

Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake.{{cite journal | vauthors = O'Carroll AM, Selby TL, Palkovits M, Lolait SJ | title = Distribution of mRNA encoding B78/apj, the rat homologue of the human APJ receptor, and its endogenous ligand apelin in brain and peripheral tissues | journal = Biochimica et Biophysica Acta | volume = 1492 | issue = 1 | pages = 72–80 | date = June 2000 | pmid = 11004481 | doi = 10.1016/S0167-4781(00)00072-5 }} Apelin injection increases water intake and apelin decreases the hypothalamic secretion of the antidiuretic hormone vasopressin.{{cite journal | vauthors = De Mota N, Lenkei Z, Llorens-Cortès C | title = Cloning, pharmacological characterization and brain distribution of the rat apelin receptor | journal = Neuroendocrinology | volume = 72 | issue = 6 | pages = 400–407 | date = December 2000 | pmid = 11146423 | doi = 10.1159/000054609 | s2cid = 39313631 | author-link3 = Catherine Llorens-Cortes }} This diuretic effect of apelin in association with its hypotensive effect participates in the homeostatic regulation of body fluid. Apelin is also detected in brain areas which control appetite, but its effects on food intake are very contradictory.{{cite journal | vauthors = Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S | title = The effects of centrally administered apelin-13 on food intake, water intake and pituitary hormone release in rats | journal = Biochemical and Biophysical Research Communications | volume = 291 | issue = 5 | pages = 1208–1212 | date = March 2002 | pmid = 11883945 | doi = 10.1006/bbrc.2002.6575 }}{{cite journal | vauthors = Sunter D, Hewson AK, Dickson SL | title = Intracerebroventricular injection of apelin-13 reduces food intake in the rat | journal = Neuroscience Letters | volume = 353 | issue = 1 | pages = 1–4 | date = December 2003 | pmid = 14642423 | doi = 10.1016/S0304-3940(03)00351-3 | s2cid = 43645121 }}{{cite journal | vauthors = O'Shea M, Hansen MJ, Tatemoto K, Morris MJ | title = Inhibitory effect of apelin-12 on nocturnal food intake in the rat | journal = Nutritional Neuroscience | volume = 6 | issue = 3 | pages = 163–167 | date = June 2003 | pmid = 12793520 | doi = 10.1080/1028415031000111273 | s2cid = 37941683 }}

Apelin is expressed and secreted by adipocytes, and its production is increased during adipocyte differentiation and is stimulated by insulin.{{cite journal | vauthors = Boucher J, Masri B, Daviaud D, Gesta S, Guigné C, Mazzucotelli A, Castan-Laurell I, Tack I, Knibiehler B, Carpéné C, Audigier Y, Saulnier-Blache JS, Valet P | title = Apelin, a newly identified adipokine up-regulated by insulin and obesity | journal = Endocrinology | volume = 146 | issue = 4 | pages = 1764–1771 | date = April 2005 | pmid = 15677759 | doi = 10.1210/en.2004-1427 | doi-access = free }} Most obese people have elevated levels of insulin, which may therefore be the reason why obese people have been reported to also have elevated levels of apelin.

Apelin receptor is expressed in several cell types of the gastro-intestinal tract : stomach enterochromaffine-like cells;{{cite journal | vauthors = Wang G, Anini Y, Wei W, Qi X, OCarroll AM, Mochizuki T, Wang HQ, Hellmich MR, Englander EW, Greeley GH | title = Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion | journal = Endocrinology | volume = 145 | issue = 3 | pages = 1342–1348 | date = March 2004 | pmid = 14670994 | doi = 10.1210/en.2003-1116 | doi-access = free }}{{cite journal | vauthors = Lambrecht NW, Yakubov I, Zer C, Sachs G | title = Transcriptomes of purified gastric ECL and parietal cells: identification of a novel pathway regulating acid secretion | journal = Physiological Genomics | volume = 25 | issue = 1 | pages = 153–165 | date = March 2006 | pmid = 16403840 | doi = 10.1152/physiolgenomics.00271.2005 }} unknown cells of endocrine pancreas, colon epithelial cells.{{cite journal | vauthors = Wang G, Kundu R, Han S, Qi X, Englander EW, Quertermous T, Greeley GH | title = Ontogeny of apelin and its receptor in the rodent gastrointestinal tract | journal = Regulatory Peptides | volume = 158 | issue = 1-3 | pages = 32–39 | date = November 2009 | pmid = 19660504 | pmc = 2761510 | doi = 10.1016/j.regpep.2009.07.016 }}

In stomach, activation of receptors on enterochromaffine-like cells by apelin secreted by parietal cells can inhibit histamine release by enterochromaffine-like cells, which in turn decreases acid secretion by parietal cells. In pancreas, apelin inhibits the insulin secretion induced by glucose.{{cite journal | vauthors = Sörhede Winzell M, Magnusson C, Ahrén B | title = The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice | journal = Regulatory Peptides | volume = 131 | issue = 1-3 | pages = 12–17 | date = November 2005 | pmid = 15970338 | doi = 10.1016/j.regpep.2005.05.004 | s2cid = 18224695 }} This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin production. Recently, receptor expression was also detected in skeletic muscle cells. Its activation is involved in glucose uptake and participates in the control of glucose blood levels glycemia.{{cite journal | vauthors = Dray C, Knauf C, Daviaud D, Waget A, Boucher J, Buléon M, Cani PD, Attané C, Guigné C, Carpéné C, Burcelin R, Castan-Laurell I, Valet P | title = Apelin stimulates glucose utilization in normal and obese insulin-resistant mice | journal = Cell Metabolism | volume = 8 | issue = 5 | pages = 437–445 | date = November 2008 | pmid = 19046574 | doi = 10.1016/j.cmet.2008.10.003 | doi-access = free }}

Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.{{cite journal | vauthors = Xie H, Tang SY, Cui RR, Huang J, Ren XH, Yuan LQ, Lu Y, Yang M, Zhou HD, Wu XP, Luo XH, Liao EY | title = Apelin and its receptor are expressed in human osteoblasts | journal = Regulatory Peptides | volume = 134 | issue = 2-3 | pages = 118–125 | date = May 2006 | pmid = 16563531 | doi = 10.1016/j.regpep.2006.02.004 | s2cid = 20819559 }}

Muscle apelin expression decreases with age in rodents and humans.{{cite journal | vauthors = Vinel C, Lukjanenko L, Batut A, Deleruyelle S, Pradère JP, Le Gonidec S, Dortignac A, Geoffre N, Pereira O, Karaz S, Lee U, Camus M, Chaoui K, Mouisel E, Bigot A, Mouly V, Vigneau M, Pagano AF, Chopard A, Pillard F, Guyonnet S, Cesari M, Burlet-Schiltz O, Pahor M, Feige JN, Vellas B, Valet P, Dray C | title = The exerkine apelin reverses age-associated sarcopenia | journal = Nature Medicine | volume = 24 | issue = 9 | pages = 1360–1371 | date = September 2018 | pmid = 30061698 | doi = 10.1038/s41591-018-0131-6 | s2cid = 51876150 }} By supplementing aged mice with exogenous apelin, Cedric Dray, Philippe Valet, and their colleagues demonstrated that the peptide was able to promote muscle hypertrophy and consequently induced a gain in strength. This study also demonstrated that apelin targets muscle cells during aging by different and complementary pathways: it acts on muscle metabolism by activating an AMPK-dependent mitochondria biogenesis, it promotes autophagy and decreases inflammation in aged mice. Moreover, apelin receptor is also present on muscle stem cells and promotes in vitro and in vivo cellular proliferation and differentiation of these cells into mature muscle cells that participate in muscle regeneration. Finally, muscle apelin could be used as a biomarker of physical exercise success in aged individuals since its production is correlated to the benefit of a chronic physical exercise in aged individuals.

In late 2022, the longevity therapeutics company BioAge announced that its licensed, orally-available apelin receptor agonist BGE-105 had greatly decreased muscle loss and sustained muscle quality and muscle protein synthesis during 10 days of bed rest in healthy volunteers aged 65 or older participating in a double-blind, placebo-controlled Phase 1b trial.{{cite web |title=BioAge Announces Positive Topline Results for BGE-105 in Phase 1b Clinical Trial Evaluating Muscle Atrophy in Older Volunteers at Bed Rest |url=https://www.businesswire.com/news/home/20221205005201/en/BioAge-Announces-Positive-Topline-Results-for-BGE-105-in-Phase-1b-Clinical-Trial-Evaluating-Muscle-Atrophy-in-Older-Volunteers-at-Bed-Rest |website=BusinessWire |date=5 December 2022 |access-date=14 January 2023}} They plan to proceed to a Phase 2 trial in older patients who are on ventilators in the intensive care unit (ICU). Such patients suffer both diaphragm atrophy (the weakening of the muscles that allow one to inhale and exhale, which atrophy dangerously due to disuse during time on a ventilator{{cite journal | vauthors = Jaber S, Petrof BJ, Jung B, Chanques G, Berthet JP, Rabuel C, Bouyabrine H, Courouble P, Koechlin-Ramonatxo C, Sebbane M, Similowski T, Scheuermann V, Mebazaa A, Capdevila X, Mornet D, Mercier J, Lacampagne A, Philips A, Matecki S | title = Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans | journal = American Journal of Respiratory and Critical Care Medicine | volume = 183 | issue = 3 | pages = 364–371 | date = February 2011 | pmid = 20813887 | doi = 10.1164/rccm.201004-0670OC }}{{cite journal | vauthors = Goligher EC, Dres M, Fan E, Rubenfeld GD, Scales DC, Herridge MS, Vorona S, Sklar MC, Rittayamai N, Lanys A, Murray A, Brace D, Urrea C, Reid WD, Tomlinson G, Slutsky AS, Kavanagh BP, Brochard LJ, Ferguson ND | title = Mechanical Ventilation-induced Diaphragm Atrophy Strongly Impacts Clinical Outcomes | journal = American Journal of Respiratory and Critical Care Medicine | volume = 197 | issue = 2 | pages = 204–213 | date = January 2018 | pmid = 28930478 | doi = 10.1164/rccm.201703-0536OC | s2cid = 3716085 }}{{cite journal | vauthors = Levine S, Nguyen T, Taylor N, Friscia ME, Budak MT, Rothenberg P, Zhu J, Sachdeva R, Sonnad S, Kaiser LR, Rubinstein NA, Powers SK, Shrager JB | title = Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans | journal = The New England Journal of Medicine | volume = 358 | issue = 13 | pages = 1327–1335 | date = March 2008 | pmid = 18367735 | doi = 10.1056/NEJMoa070447 | doi-access = free }}) and critical illness myopathy (the broad weakening of the muscles during extended bed rest). Each of these conditions are associated with poor functional recovery and substantially increased risk of death after illness.

{{Reflist|30em}}

{{refbegin | colwidth = 30em}}

• {{cite journal | vauthors = Lee DK, George SR, O'Dowd BF | title = Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity | journal = Trends in Pharmacological Sciences | volume = 27 | issue = 4 | pages = 190–194 | date = April 2006 | pmid = 16530855 | doi = 10.1016/j.tips.2006.02.006 }}
• {{cite journal | vauthors = Lee DK, Saldivia VR, Nguyen T, Cheng R, George SR, O'Dowd BF | title = Modification of the terminal residue of apelin-13 antagonizes its hypotensive action | journal = Endocrinology | volume = 146 | issue = 1 | pages = 231–236 | date = January 2005 | pmid = 15486224 | doi = 10.1210/en.2004-0359 | doi-access = free }}
• {{cite journal | vauthors = Lee DK, Lança AJ, Cheng R, Nguyen T, Ji XD, Gobeil F, Chemtob S, George SR, O'Dowd BF | title = Agonist-independent nuclear localization of the Apelin, angiotensin AT1, and bradykinin B2 receptors | journal = The Journal of Biological Chemistry | volume = 279 | issue = 9 | pages = 7901–7908 | date = February 2004 | pmid = 14645236 | doi = 10.1074/jbc.M306377200 | doi-access = free }}
• {{cite journal | vauthors = O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T | title = A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11 | journal = Gene | volume = 136 | issue = 1-2 | pages = 355–360 | date = December 1993 | pmid = 8294032 | doi = 10.1016/0378-1119(93)90495-O }}
• {{cite journal | vauthors = Chun HJ, Ali ZA, Kojima Y, Kundu RK, Sheikh AY, Agrawal R, Zheng L, Leeper NJ, Pearl NE, Patterson AJ, Anderson JP, Tsao PS, Lenardo MJ, Ashley EA, Quertermous T | title = Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis | journal = The Journal of Clinical Investigation | volume = 118 | issue = 10 | pages = 3343–3354 | date = October 2008 | pmid = 18769630 | pmc = 2525695 | doi = 10.1172/JCI34871 }}
• {{cite journal | vauthors = Barnes G, Japp AG, Newby DE | title = Translational promise of the apelin--APJ system | journal = Heart | volume = 96 | issue = 13 | pages = 1011–1016 | date = July 2010 | pmid = 20584856 | doi = 10.1136/hrt.2009.191122 | s2cid = 21522978 }}

{{refend}}

• {{MeshName|Apelin+protein,+human}}
• {{cite web | url = http://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1329 | title = Apelin | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2007-10-25 | archive-date = 2021-08-16 | archive-url = https://web.archive.org/web/20210816094527/https://www.iuphar-db.org/GPCR/ChapterMenuForward?chapterID=1329 | url-status = dead }}
• {{UCSC gene info|APLN}}

Category:Proteins