Apelin is a peptide that was identified in 1998 by Professor M. Fujino’s team.
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. Recently, 46 different apelin peptides ranging from apelin 55 (proapelin) to apelin 12 have been identified in bovine colostrum, including C-ter truncated isoforms.
The sites of receptor expression are clearly linked to the different functions played by apelin in the organism.
Vascular expression of the receptor participates in the control of blood pressure and its activation promotes the formation of new blood vessels (angiogenesis). The hypotensive effect of apelin results from the activation of receptors expressed at the surface of endothelial cells. This activation induces the release of NO, 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 have suggested the existence of a balance between angiotensin II signalling, which increases blood pressure and apelin signalling, which lowers blood pressure. The angiogenic activity is the consequence of apelin action on the proliferation and migration of the endothelial cells. Apelin activates inside the cell transduction cascades (ERKs, Akt, and p70S6kinase phosphorylation), which lead to the proliferation of endothelial cells and the formation of new blood vessels. Knockout of the apelin gene is associated with a delay in the development of the retinal vasculature.
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. Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility. Aged apelin knockout mice develop progressive impairment of cardiac contractility. 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.
The plasma concentration of apelin is shown to increase during exercise.. Paradoxically, exogenous apelin in healthy volunteers reduced peak VO2 in an endurance test.
Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake. Apelin injection increases water intake and apelin decreases the hypothalamic secretion of the antidiuretichormonevasopressin. 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.
Apelin is expressed and secreted by adipocytes, and its production is increased during adipocyte differentiation and is stimulated by insulin. 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; unknown cells of endocrine pancreas,colon epithelial cells.
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. 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.
Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.
Muscle apelin expression decreases with age in rodents and humans. By supplementing aged mice with exogenous apelin, the team of Dr C. Dray shown 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 proliferation and differenciation of these cells into mature muscle cells participating to muscle regeneration. Finally, muscle apelin could be used a biomarker of physical exercise success in aged individual since its production is correlated to the benefit of a chronic physical exercise in aged individuals.
^ abcTatemoto 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 (1998). "Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor". Biochem. Biophys. Res. Commun. 251 (2): 471–6. doi:10.1006/bbrc.1998.9489. PMID9792798.
^ abSzokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, Pikkarainen S, Piuhola J, Rysä J, Tóth M, Ruskoaho H (2002). "Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility". Circ. Res. 91 (5): 434–40. doi:10.1161/01.RES.0000033522.37861.69. PMID12215493.
^O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T (December 1993). "A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11". Gene. 136 (1–2): 355–60. doi:10.1016/0378-1119(93)90495-O. PMID8294032.
^Devic E, Paquereau L, Vernier P, Knibiehler B, Audigier Y (October 1996). "Expression of a new G protein-coupled receptor X-msr is associated with an endothelial lineage in Xenopus laevis". Mech. Dev. 59 (2): 129–40. doi:10.1016/0925-4773(96)00585-0. PMID8951791.
^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): 2875–84. doi:10.1002/rcm.4718. PMID20857448.
^Mesmin C, Fenaille F, Becher F, Tabet JC, Ezan E (2011). "Identification and characterization of apelin peptides in bovine colostrum and milk by liquid chromatography-mass spectrometry". J Proteome Res. 10 (11): 5222–31. doi:10.1021/pr200725x. PMID21939284.
^ abDevic E, Rizzoti K, Bodin S, Knibiehler B, Audigier Y (June 1999). "Amino acid sequence and embryonic expression of msr/apj, the mouse homolog of Xenopus X-msr and human APJ". Mech. Dev. 84 (1–2): 199–203. doi:10.1016/S0925-4773(99)00081-7. PMID10473142.
^ abcSaint-Geniez M, Masri B, Malecaze F, Knibiehler B, Audigier Y (January 2002). "Expression of the murine msr/apj receptor and its ligand apelin is upregulated during formation of the retinal vessels". Mech. Dev. 110 (1–2): 183–6. doi:10.1016/S0925-4773(01)00558-5. PMID11744380.
^ abMasri B, Morin N, Cornu M, Knibiehler B, Audigier Y (December 2004). "Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells". FASEB J. 18 (15): 1909–11. doi:10.1096/fj.04-1930fje. PMID15385434.
^ abKasai A, Shintani N, Oda M, Kakuda M, Hashimoto H, Matsuda T, Hinuma S, Baba A (December 2004). "Apelin is a novel angiogenic factor in retinal endothelial cells". Biochem. Biophys. Res. Commun. 325 (2): 395–400. doi:10.1016/j.bbrc.2004.10.042. PMID15530405.
^Cox CM, D'Agostino SL, Miller MK, Heimark RL, Krieg PA (August 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): 177–89. doi:10.1016/j.ydbio.2006.04.452. PMID16750822.
^Tatemoto K, Takayama K, Zou MX, Kumaki I, Zhang W, Kumano K, Fujimiya M (June 2001). "The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism". Regul. Pept. 99 (2–3): 87–92. doi:10.1016/S0167-0115(01)00236-1. PMID11384769.
^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 (June 2004). "Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo". J. Biol. Chem. 279 (25): 26274–9. doi:10.1074/jbc.M404149200. PMID15087458.
^Masri B, Lahlou H, Mazarguil H, Knibiehler B, Audigier Y (January 2002). "Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein". Biochem. Biophys. Res. Commun. 290 (1): 539–45. doi:10.1006/bbrc.2001.6230. PMID11779205.
^Kasai A, Shintani N, Kato H, Matsuda S, Gomi F, Haba R, Hashimoto H, Kakuda M, Tano Y, Baba A (October 2008). "Retardation of retinal vascular development in apelin-deficient mice". Arterioscler. Thromb. Vasc. Biol. 28 (10): 1717–22. doi:10.1161/ATVBAHA.108.163402. PMID18599802.
^Scott IC, Masri B, D'Amico LA, Jin SW, Jungblut B, Wehman AM, Baier H, Audigier Y, Stainier DY (March 2007). "The g protein-coupled receptor agtrl1b regulates early development of myocardial progenitors". Dev. Cell. 12 (3): 403–13. doi:10.1016/j.devcel.2007.01.012. PMID17336906.
^Zeng XX, Wilm TP, Sepich DS, Solnica-Krezel L (March 2007). "Apelin and its receptor control heart field formation during zebrafish gastrulation". Dev. Cell. 12 (3): 391–402. doi:10.1016/j.devcel.2007.01.011. PMID17336905.
^Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, Woo YJ (September 2004). "Apelin has in vivo inotropic effects on normal and failing hearts". Circulation. 110 (11 Suppl 1): II187–93. doi:10.1161/01.CIR.0000138382.57325.5c. PMID15364861.
^Kuba K, Zhang L, Imai Y, Arab S, Chen M, Maekawa Y, Leschnik M, Leibbrandt A, Markovic M, Makovic 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 (August 2007). "Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload". Circ. Res. 101 (4): e32–42. doi:10.1161/CIRCRESAHA.107.158659. PMID17673668.
^Principe A, Melgar-Lesmes P, Fernández-Varo G, Del Arbol LR, Ros J, Morales-Ruiz M, Bernardi M, Arroyo V, Jiménez W (2008). "The hepatic apelin system: A new therapeutic target for liver disease". Hepatology. 48 (4): 1193–1201. doi:10.1002/hep.22467. PMID18816630.
^Kechyn S, Barnes G, Howard L (2015). "Assessing dynamic changes in plasma apelin concentration in response to maximal exercise in man". European Respiratory Journal. 46: PA2316. doi:10.1183/13993003.congress-2015.PA2316.
^Kechyn, Svyatoslav; Barnes, Gareth; Thongmee, Akaphot; Howard, Luke (September 2015). "Effect of apelin on cardiopulmonary performance during endurance exercise". European Respiratory Journal (46 suppl 59): 2241. doi:10.1183/13993003.congress-2015.PA2241.
^O'Carroll AM, Selby TL, Palkovits M, Lolait SJ (June 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 (1): 72–80. doi:10.1016/S0167-4781(00)00072-5. PMID11004481.
^De Mota N, Lenkei Z, Llorens-Cortès C (December 2000). "Cloning, pharmacological characterization and brain distribution of the rat apelin receptor". Neuroendocrinology. 72 (6): 400–7. doi:10.1159/000054609. PMID11146423.
^Taheri S, Murphy K, Cohen M, Sujkovic E, Kennedy A, Dhillo W, Dakin C, Sajedi A, Ghatei M, Bloom S (March 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): 1208–12. doi:10.1006/bbrc.2002.6575. PMID11883945.
^ abcBoucher 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 (April 2005). "Apelin, a newly identified adipokine up-regulated by insulin and obesity". Endocrinology. 146 (4): 1764–71. doi:10.1210/en.2004-1427. PMID15677759.
^Wang G, Anini Y, Wei W, Qi X, OCarroll AM, Mochizuki T, Wang HQ, Hellmich MR, Englander EW, Greeley GH (March 2004). "Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion". Endocrinology. 145 (3): 1342–8. doi:10.1210/en.2003-1116. PMID14670994.
^ abLambrecht NW, Yakubov I, Zer C, Sachs G (March 2006). "Transcriptomes of purified gastric ECL and parietal cells: identification of a novel pathway regulating acid secretion". Physiol. Genomics. 25 (1): 153–65. doi:10.1152/physiolgenomics.00271.2005. PMID16403840.
^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 (November 2008). "Apelin stimulates glucose utilization in normal and obese insulin-resistant mice". Cell Metab. 8 (5): 437–45. doi:10.1016/j.cmet.2008.10.003. PMID19046574.
^Xie H, Tang SY, Cui RR, Huang J, Ren XH, Yuan LQ, Lu Y, Yang M, Zhou HD, Wu XP, Luo XH, Liao EY (May 2006). "Apelin and its receptor are expressed in human osteoblasts". Regul. Pept. 134 (2–3): 118–25. doi:10.1016/j.regpep.2006.02.004. PMID16563531.
Lee DK, George SR, O'Dowd BF (2006). "Unravelling the roles of the apelin system: prospective therapeutic applications in heart failure and obesity". Trends Pharmacol. Sci. 27 (4): 190–4. doi:10.1016/j.tips.2006.02.006. PMID16530855.
Lee DK, Saldivia VR, Nguyen T, Cheng R, George SR, O'Dowd BF (2005). "Modification of the terminal residue of apelin-13 antagonizes its hypotensive action". Endocrinology. 146 (1): 231–6. doi:10.1210/en.2004-0359. PMID15486224.
Lee DK, Lança AJ, Cheng R, Nguyen T, Ji XD, Gobeil F, Chemtob S, George SR, O'Dowd BF (2004). "Agonist-independent nuclear localization of the Apelin, angiotensin AT1, and bradykinin B2 receptors". J. Biol. Chem. 279 (9): 7901–8. doi:10.1074/jbc.M306377200. PMID14645236.
O'Dowd BF, Heiber M, Chan A, Heng HH, Tsui LC, Kennedy JL, Shi X, Petronis A, George SR, Nguyen T (1993). "A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11". Gene. 136 (1–2): 355–60. doi:10.1016/0378-1119(93)90495-O. PMID8294032.