Biology:Apelin

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Apelin (also known as APLN) is a peptide that in humans is encoded by the APLN gene.[1] Apelin is one of two endogenous ligands for the G-protein-coupled APJ receptor[2][3][4][5][6] that is expressed at the surface of some cell types.[7] It is widely expressed in various organs such as the heart, lung, kidney, liver, adipose tissue, gastrointestinal tract, brain, adrenal glands, endothelium, and human plasma.

Discovery

Apelin is a peptide hormone that was identified in 1998 by Masahiko Fujino and his colleagues at Gunma University and Takeda Pharmaceutical Company.[1] In 2013, a second peptide hormone named Elabela was found by Bruno Reversade to also act as an endogenous ligand to the APLNR.

Biosynthesis

The apelin gene encodes a pre-proprotein of 77 amino acids,[1] 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.[8] Recently, 46 different apelin peptides ranging from apelin 55 (proapelin) to apelin 12 have been identified in bovine colostrum, including C-ter truncated isoforms.[9]

Physiological functions

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

Vascular

Vascular expression of the receptor[10][11] participates in the control of blood pressure[2] and its activation promotes the formation of new blood vessels (angiogenesis).[11][12][13][14] The blood pressure-lowering (hypotensive) effect of apelin results from the activation of receptors expressed at the surface of endothelial cells.[10][11] This activation induces the release of nitric oxide (NO),[15] 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[16] 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,[12][17] which lead to the proliferation of endothelial cells and the formation of new blood vessels.[13] Genetic knockout of the apelin gene is associated with a delay in the development of the retinal vasculature.[18]

Cardiac

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.[19][20] Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.[3][21][22] Aged apelin knockout mice develop progressive impairment of cardiac contractility.[23] 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.[24]

Exercise

The plasma concentration of apelin is shown to increase during exercise.[25] Paradoxically, exogenous apelin in healthy volunteers reduced VO2 peak (peak oxygen consumption) in an endurance test.[26]

Brain

Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake.[2][27][28] Apelin injection increases water intake[2] and apelin decreases the hypothalamic secretion of the antidiuretic hormone vasopressin.[29] 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.[30][31][32]

Adipose tissue

Apelin is expressed and secreted by adipocytes, and its production is increased during adipocyte differentiation and is stimulated by insulin.[33] 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.[33]

Digestive

Apelin receptor is expressed in several cell types of the gastro-intestinal tract : stomach enterochromaffine-like cells;[34][35] unknown cells of endocrine pancreas,[36] colon epithelial cells.[37] 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.[35] In pancreas, apelin inhibits the insulin secretion induced by glucose.[38] This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin production.[33] 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.[39]

Bone

Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.[40]

Muscle aging

Muscle apelin expression decreases with age in rodents and humans.[41] 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.[41] 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.[41] 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.[41]

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.[42] 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[43][44][45]) 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.[42]

References

  1. ↑ 1.0 1.1 1.2 "Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor". Biochem. Biophys. Res. Commun. 251 (2): 471–6. 1998. doi:10.1006/bbrc.1998.9489. PMID 9792798. 
  2. ↑ 2.0 2.1 2.2 2.3 "Characterization of apelin, the ligand for the APJ receptor". J. Neurochem. 74 (1): 34–41. 2000. doi:10.1046/j.1471-4159.2000.0740034.x. PMID 10617103. 
  3. ↑ 3.0 3.1 "Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility". Circ. Res. 91 (5): 434–40. 2002. doi:10.1161/01.RES.0000033522.37861.69. PMID 12215493. 
  4. ↑ "Emerging roles of apelin in biology and medicine". Pharmacol. Ther. 107 (2): 198–211. 2005. doi:10.1016/j.pharmthera.2005.04.001. PMID 15907343. 
  5. ↑ "A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11". Gene 136 (1–2): 355–60. December 1993. doi:10.1016/0378-1119(93)90495-O. PMID 8294032. 
  6. ↑ "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. October 1996. doi:10.1016/0925-4773(96)00585-0. PMID 8951791. 
  7. ↑ Audigier Y (2006-04-07). "Apelin Receptor". UCSD Nature Molecule Pages. doi:10.1038/mp.a000304.01. http://www.signaling-gateway.org/molecule/query?afcsid=A000304&mpv=1. Retrieved 2009-09-02. 
  8. ↑ "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. 2010. doi:10.1002/rcm.4718. PMID 20857448. Bibcode: 2010RCMS...24.2875M. 
  9. ↑ "Identification and characterization of apelin peptides in bovine colostrum and milk by liquid chromatography-mass spectrometry.". J Proteome Res 10 (11): 5222–31. 2011. doi:10.1021/pr200725x. PMID 21939284. 
  10. ↑ 10.0 10.1 "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. June 1999. doi:10.1016/S0925-4773(99)00081-7. PMID 10473142. 
  11. ↑ 11.0 11.1 11.2 "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. January 2002. doi:10.1016/S0925-4773(01)00558-5. PMID 11744380. 
  12. ↑ 12.0 12.1 "Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells". FASEB J. 18 (15): 1909–11. December 2004. doi:10.1096/fj.04-1930fje. PMID 15385434. 
  13. ↑ 13.0 13.1 "Apelin is a novel angiogenic factor in retinal endothelial cells". Biochem. Biophys. Res. Commun. 325 (2): 395–400. December 2004. doi:10.1016/j.bbrc.2004.10.042. PMID 15530405. 
  14. ↑ "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. August 2006. doi:10.1016/j.ydbio.2006.04.452. PMID 16750822. 
  15. ↑ "The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism". Regul Pept 99 (2–3): 87–92. June 2001. doi:10.1016/S0167-0115(01)00236-1. PMID 11384769. 
  16. ↑ "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. June 2004. doi:10.1074/jbc.M404149200. PMID 15087458. 
  17. ↑ "Apelin (65-77) activates extracellular signal-regulated kinases via a PTX-sensitive G protein". Biochem. Biophys. Res. Commun. 290 (1): 539–45. January 2002. doi:10.1006/bbrc.2001.6230. PMID 11779205. 
  18. ↑ "Retardation of retinal vascular development in apelin-deficient mice". Arterioscler. Thromb. Vasc. Biol. 28 (10): 1717–22. October 2008. doi:10.1161/ATVBAHA.108.163402. PMID 18599802. 
  19. ↑ "The g protein-coupled receptor agtrl1b regulates early development of myocardial progenitors". Dev. Cell 12 (3): 403–13. March 2007. doi:10.1016/j.devcel.2007.01.012. PMID 17336906. 
  20. ↑ "Apelin and its receptor control heart field formation during zebrafish gastrulation". Dev. Cell 12 (3): 391–402. March 2007. doi:10.1016/j.devcel.2007.01.011. PMID 17336905. 
  21. ↑ "Apelin has in vivo inotropic effects on normal and failing hearts". Circulation 110 (11 Suppl 1): II187–93. September 2004. doi:10.1161/01.CIR.0000138382.57325.5c. PMID 15364861. 
  22. ↑ "The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo". Cardiovasc. Res. 65 (1): 73–82. January 2005. doi:10.1016/j.cardiores.2004.08.018. PMID 15621035. 
  23. ↑ "Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload". Circ. Res. 101 (4): e32–42. August 2007. doi:10.1161/CIRCRESAHA.107.158659. PMID 17673668. 
  24. ↑ "The hepatic apelin system: A new therapeutic target for liver disease". Hepatology 48 (4): 1193–1201. 2008. doi:10.1002/hep.22467. PMID 18816630. 
  25. ↑ "Assessing dynamic changes in plasma apelin concentration in response to maximal exercise in man". European Respiratory Journal 46: PA2316. 2015. doi:10.1183/13993003.congress-2015.PA2316. 
  26. ↑ 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. 
  27. ↑ "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. June 2000. doi:10.1016/S0167-4781(00)00072-5. PMID 11004481. 
  28. ↑ De Mota et al., 2000
  29. ↑ "Cloning, pharmacological characterization and brain distribution of the rat apelin receptor". Neuroendocrinology 72 (6): 400–7. December 2000. doi:10.1159/000054609. PMID 11146423. 
  30. ↑ "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. March 2002. doi:10.1006/bbrc.2002.6575. PMID 11883945. 
  31. ↑ "Intracerebroventricular injection of apelin-13 reduces food intake in the rat". Neurosci. Lett. 353 (1): 1–4. December 2003. doi:10.1016/S0304-3940(03)00351-3. PMID 14642423. 
  32. ↑ "Inhibitory effect of apelin-12 on nocturnal food intake in the rat". Nutr Neurosci 6 (3): 163–7. June 2003. doi:10.1080/1028415031000111273. PMID 12793520. 
  33. ↑ 33.0 33.1 33.2 "Apelin, a newly identified adipokine up-regulated by insulin and obesity". Endocrinology 146 (4): 1764–71. April 2005. doi:10.1210/en.2004-1427. PMID 15677759. 
  34. ↑ "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. March 2004. doi:10.1210/en.2003-1116. PMID 14670994. 
  35. ↑ 35.0 35.1 "Transcriptomes of purified gastric ECL and parietal cells: identification of a novel pathway regulating acid secretion". Physiol. Genomics 25 (1): 153–65. March 2006. doi:10.1152/physiolgenomics.00271.2005. PMID 16403840. 
  36. ↑ Sorhede Winzell et al., 2005
  37. ↑ "Ontogeny of apelin and its receptor in the rodent gastrointestinal tract". Regul. Pept. 158 (1–3): 32–9. August 2009. doi:10.1016/j.regpep.2009.07.016. PMID 19660504. 
  38. ↑ "The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice". Regul. Pept. 131 (1–3): 12–7. November 2005. doi:10.1016/j.regpep.2005.05.004. PMID 15970338. http://lup.lub.lu.se/record/139874. 
  39. ↑ "Apelin stimulates glucose utilization in normal and obese insulin-resistant mice". Cell Metab. 8 (5): 437–45. November 2008. doi:10.1016/j.cmet.2008.10.003. PMID 19046574. 
  40. ↑ "Apelin and its receptor are expressed in human osteoblasts". Regul. Pept. 134 (2–3): 118–25. May 2006. doi:10.1016/j.regpep.2006.02.004. PMID 16563531. 
  41. ↑ 41.0 41.1 41.2 41.3 Vinel, Claire; Lukjanenko, Laura; Batut, Aurelie; Deleruyelle, Simon; Pradère, Jean-Philippe; Le Gonidec, Sophie; Dortignac, Allizée; Geoffre, Nancy et al. (30 July 2018). "The exerkine apelin reverses age-associated sarcopenia.". Nature Medicine 24 (9): 1360–1371. doi:10.1038/s41591-018-0131-6. PMID 30061698. 
  42. ↑ 42.0 42.1 "BioAge Announces Positive Topline Results for BGE-105 in Phase 1b Clinical Trial Evaluating Muscle Atrophy in Older Volunteers at Bed Rest". 5 December 2022. 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. 
  43. ↑ "Rapidly progressive diaphragmatic weakness and injury during mechanical ventilation in humans". American Journal of Respiratory and Critical Care Medicine 183 (3): 364–371. February 2011. doi:10.1164/rccm.201004-0670OC. PMID 20813887. 
  44. ↑ "Mechanical Ventilation-induced Diaphragm Atrophy Strongly Impacts Clinical Outcomes". American Journal of Respiratory and Critical Care Medicine 197 (2): 204–213. January 2018. doi:10.1164/rccm.201703-0536OC. PMID 28930478. 
  45. ↑ "Rapid disuse atrophy of diaphragm fibers in mechanically ventilated humans". The New England Journal of Medicine 358 (13): 1327–1335. March 2008. doi:10.1056/NEJMoa070447. PMID 18367735. 

Further reading

External links



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