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=== Vascular ===
=== Vascular ===


Vascular expression of the receptor<ref name="Devic_1999">{{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 = Mech. Dev. | volume = 84 | issue = 1–2 | pages = 199–203 |date=June 1999 | pmid = 10473142 | doi = 10.1016/S0925-4773(99)00081-7| url = }}</ref><ref name="Saint-Geniez_2002">{{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 = Mech. Dev. | volume = 110 | issue = 1–2 | pages = 183–6 |date=January 2002 | pmid = 11744380 | doi = 10.1016/S0925-4773(01)00558-5| url = }}</ref> participates in the control of [[blood pressure]]<ref name="Lee_2000"/> and its activation promotes the formation of new blood vessels ([[angiogenesis]]).<ref name="Saint-Geniez_2002"/><ref name="Masri_2004">{{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 J. | volume = 18 | issue = 15 | pages = 1909–11 |date=December 2004 | pmid = 15385434 | doi = 10.1096/fj.04-1930fje | url = }}</ref><ref name="Kasai_2004">{{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 = Biochem. Biophys. Res. Commun. | volume = 325 | issue = 2 | pages = 395–400 |date=December 2004 | pmid = 15530405 | doi = 10.1016/j.bbrc.2004.10.042 | url = }}</ref><ref name="pmid16750822">{{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 = Dev. Biol. | volume = 296 | issue = 1 | pages = 177–89 |date=August 2006 | pmid = 16750822 | doi = 10.1016/j.ydbio.2006.04.452 | url = }}</ref>  The [[hypotensive]] effect of apelin results from the activation of receptors expressed at the surface of [[endothelial cells]].<ref name="Devic_1999"/><ref name="Saint-Geniez_2002"/> This activation induces the release of NO,<ref name="pmid11384769">{{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 = Regul. Pept. | volume = 99 | issue = 2–3 | pages = 87–92 |date=June 2001 | pmid = 11384769 | doi = 10.1016/S0167-0115(01)00236-1| url = }}</ref> 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<ref name="pmid15087458">{{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 = J. Biol. Chem. | volume = 279 | issue = 25 | pages = 26274–9 |date=June 2004 | pmid = 15087458 | doi = 10.1074/jbc.M404149200 | url = }}</ref> 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),<ref name="Masri_2004"/><ref name="pmid11779205">{{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 = Biochem. Biophys. Res. Commun. | volume = 290 | issue = 1 | pages = 539–45 |date=January 2002 | pmid = 11779205 | doi = 10.1006/bbrc.2001.6230 | url = }}</ref> which lead to the proliferation of endothelial cells and the formation of new blood vessels<ref name="Kasai_2004"/> It is interesting that knockout of apelin gene is associated with a delay in the development of the retinal vasculature.<ref name="pmid18599802">{{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 = Arterioscler. Thromb. Vasc. Biol. | volume = 28 | issue = 10 | pages = 1717–22 |date=October 2008 | pmid = 18599802 | doi = 10.1161/ATVBAHA.108.163402 | url = }}</ref>
Vascular expression of the receptor<ref name="Devic_1999">{{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 = Mech. Dev. | volume = 84 | issue = 1–2 | pages = 199–203 |date=June 1999 | pmid = 10473142 | doi = 10.1016/S0925-4773(99)00081-7| url = }}</ref><ref name="Saint-Geniez_2002">{{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 = Mech. Dev. | volume = 110 | issue = 1–2 | pages = 183–6 |date=January 2002 | pmid = 11744380 | doi = 10.1016/S0925-4773(01)00558-5| url = }}</ref> participates in the control of [[blood pressure]]<ref name="Lee_2000"/> and its activation promotes the formation of new blood vessels ([[angiogenesis]]).<ref name="Saint-Geniez_2002"/><ref name="Masri_2004">{{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 J. | volume = 18 | issue = 15 | pages = 1909–11 |date=December 2004 | pmid = 15385434 | doi = 10.1096/fj.04-1930fje | url = }}</ref><ref name="Kasai_2004">{{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 = Biochem. Biophys. Res. Commun. | volume = 325 | issue = 2 | pages = 395–400 |date=December 2004 | pmid = 15530405 | doi = 10.1016/j.bbrc.2004.10.042 | url = }}</ref><ref name="pmid16750822">{{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 = Dev. Biol. | volume = 296 | issue = 1 | pages = 177–89 |date=August 2006 | pmid = 16750822 | doi = 10.1016/j.ydbio.2006.04.452 | url = }}</ref>  The [[hypotensive]] effect of apelin results from the activation of receptors expressed at the surface of [[endothelial cells]].<ref name="Devic_1999"/><ref name="Saint-Geniez_2002"/> This activation induces the release of NO,<ref name="pmid11384769">{{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 = Regul. Pept. | volume = 99 | issue = 2–3 | pages = 87–92 |date=June 2001 | pmid = 11384769 | doi = 10.1016/S0167-0115(01)00236-1| url = }}</ref> 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<ref name="pmid15087458">{{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 = J. Biol. Chem. | volume = 279 | issue = 25 | pages = 26274–9 |date=June 2004 | pmid = 15087458 | doi = 10.1074/jbc.M404149200 | url = }}</ref> 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),<ref name="Masri_2004"/><ref name="pmid11779205">{{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 = Biochem. Biophys. Res. Commun. | volume = 290 | issue = 1 | pages = 539–45 |date=January 2002 | pmid = 11779205 | doi = 10.1006/bbrc.2001.6230 | url = }}</ref> which lead to the proliferation of endothelial cells and the formation of new blood vessels.<ref name="Kasai_2004"/> Knockout of the apelin gene is associated with a delay in the development of the retinal vasculature.<ref name="pmid18599802">{{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 = Arterioscler. Thromb. Vasc. Biol. | volume = 28 | issue = 10 | pages = 1717–22 |date=October 2008 | pmid = 18599802 | doi = 10.1161/ATVBAHA.108.163402 | url = }}</ref>


=== Cardiac ===
=== 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.<ref name="pmid17336906">{{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 = Dev. Cell | volume = 12 | issue = 3 | pages = 403–13 |date=March 2007 | pmid = 17336906 | doi = 10.1016/j.devcel.2007.01.012 | url = }}</ref><ref name="pmid17336905">{{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 = Dev. Cell | volume = 12 | issue = 3 | pages = 391–402 |date=March 2007 | pmid = 17336905 | doi = 10.1016/j.devcel.2007.01.011 | url = }}</ref> Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.<ref name="pmid12215493"/><ref name="pmid15364861">{{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 = II187–93 |date=September 2004 | pmid = 15364861 | doi = 10.1161/01.CIR.0000138382.57325.5c | url = }}</ref><ref name="pmid15621035">{{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 = Cardiovasc. Res. | volume = 65 | issue = 1 | pages = 73–82 |date=January 2005 | pmid = 15621035 | pmc = 2517138 | doi = 10.1016/j.cardiores.2004.08.018 | url = }}</ref> Aged apelin knockout mice develop progressive impairment of cardiac contractility.<ref name="pmid17673668">{{cite journal |vauthors=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 | title = Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload | journal = Circ. Res. | volume = 101 | issue = 4 | pages = e32–42 |date=August 2007 | pmid = 17673668 | doi = 10.1161/CIRCRESAHA.107.158659 | url = }}</ref>  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]].<ref name="pmid18816630">{{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 | year = 2008 | pmid = 18816630 | doi = 10.1002/hep.22467 }}</ref>
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.<ref name="pmid17336906">{{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 = Dev. Cell | volume = 12 | issue = 3 | pages = 403–13 |date=March 2007 | pmid = 17336906 | doi = 10.1016/j.devcel.2007.01.012 | url = }}</ref><ref name="pmid17336905">{{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 = Dev. Cell | volume = 12 | issue = 3 | pages = 391–402 |date=March 2007 | pmid = 17336905 | doi = 10.1016/j.devcel.2007.01.011 | url = }}</ref> Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.<ref name="pmid12215493"/><ref name="pmid15364861">{{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 = II187–93 |date=September 2004 | pmid = 15364861 | doi = 10.1161/01.CIR.0000138382.57325.5c | url = }}</ref><ref name="pmid15621035">{{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 = Cardiovasc. Res. | volume = 65 | issue = 1 | pages = 73–82 |date=January 2005 | pmid = 15621035 | pmc = 2517138 | doi = 10.1016/j.cardiores.2004.08.018 | url = }}</ref> Aged apelin knockout mice develop progressive impairment of cardiac contractility.<ref name="pmid17673668">{{cite journal |vauthors=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 | title = Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload | journal = Circ. Res. | volume = 101 | issue = 4 | pages = e32–42 |date=August 2007 | pmid = 17673668 | doi = 10.1161/CIRCRESAHA.107.158659 | url = }}</ref>  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]].<ref name="pmid18816630">{{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 | year = 2008 | pmid = 18816630 | doi = 10.1002/hep.22467 }}</ref>
=== Exercise ===
The plasma concentration of apelin is shown to increase during exercise.<ref name="zzzz">{{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}}</ref>. Paradoxically,exogenous apelin in healthy volunteers reduced peak VO2 in an endurance test.<ref>{{cite journal |last1=Kechyn |first1=Svyatoslav |last2=Barnes |first2=Gareth |last3=Thongmee |first3=Akaphot |last4=Howard |first4=Luke |title=Effect of apelin on cardiopulmonary performance during endurance exercise |journal=European Respiratory Journal |date=September 2015 |issue=46 suppl 59 |pages=2241 |doi=10.1183/13993003.congress-2015.PA2241}}</ref>


=== Brain ===
=== Brain ===
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===Adipose tissue===
===Adipose tissue===
Apelin is expressed and secreted by [[adipocyte]]s, and its production is increased during adipocyte differentiation and is stimulated by [[insulin]].<ref name="Boucher2005">{{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. 2005 Apr|date=April 2005|volume=146|issue=4|pages=1764-71|doi=10.1210/en.2004-1427|pmid=15677759|url=http://press.endocrine.org/doi/full/10.1210/en.2004-1427|accessdate=30 June 2016}}</ref> 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.<ref name="Boucher2005"/>
Apelin is expressed and secreted by [[adipocyte]]s, and its production is increased during adipocyte differentiation and is stimulated by [[insulin]].<ref name="Boucher2005">{{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 |date=April 2005|volume=146|issue=4|pages=1764–71|doi=10.1210/en.2004-1427|pmid=15677759|url=http://press.endocrine.org/doi/full/10.1210/en.2004-1427|accessdate=30 June 2016}}</ref> 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.<ref name="Boucher2005"/>


=== Digestive ===
=== Digestive ===
Line 38: Line 42:


Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.<ref name="pmid16563531">{{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 = Regul. Pept. | volume = 134 | issue = 2–3 | pages = 118–25 |date=May 2006 | pmid = 16563531 | doi = 10.1016/j.regpep.2006.02.004 | url = }}</ref>
Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.<ref name="pmid16563531">{{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 = Regul. Pept. | volume = 134 | issue = 2–3 | pages = 118–25 |date=May 2006 | pmid = 16563531 | doi = 10.1016/j.regpep.2006.02.004 | url = }}</ref>
=== Muscle aging ===
Muscle apelin expression decreases with age in rodents and humans<ref name="vinel_2018">{{cite journal |last1=Vinel |first1=Claire |last2=Lukjanenko |first2=Laura |last3=Batut |first3=Aurelie |last4=Deleruyelle |first4=Simon |last5=Pradère |first5=Jean-Philippe |last6=Le Gonidec |first6=Sophie |last7=Dortignac |first7=Allizée |last8=Geoffre |first8=Nancy |last9=Pereira |first9=Ophélie |last10=Karaz |first10=Sonia |last11=Lee |first11=Umi |last12=Camus |first12=Mylène |last13=Chaoui |first13=Karima |last14=Mouisel |first14=Etienne |last15=Bigot |first15=Anne |last16=Mouly |first16=Vincent |last17=Vigneau |first17=Mathieu |last18=Pagano |first18=Allan |last19=Chopard |first19=Angèle |last20=Pillard |first20=Fabien |last21=Guyonnet |first21=Sophie |last22=Cesari |first22=Matteo |last23=Burlet |first23=Odile |last24=Pahor |first24=Marco |last25=Feige |first25=Jerome |last26=Vellas |first26=Bruno |last27=Valet |first27=Philippe |last28=Dray |first28=Cedric |title=The exerkine apelin reverses age-associated sarcopenia. |journal=Nature Medicine |date=30 July 2018 |doi=10.1038/s41591-018-0131-6 |pmid=30061698 }}</ref>. 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<ref name="vinel_2018"/>. 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<ref name="vinel_2018"/>. 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 corelated to the benefit of a chronic physical exercise in aged individuals<ref name="vinel_2018"/>.


== References ==
== References ==

Latest revision as of 11:52, 7 November 2018

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View/Edit Human

Apelin (also known as APLN) is a peptide that in humans is encoded by the APLN gene.[1] Apelin is the endogenous ligand 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 that was identified in 1998 by Professor M. Fujino’s team.[1]

Biosynthesis

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 clearly 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 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 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 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),[12][17] which lead to the proliferation of endothelial cells and the formation of new blood vessels.[13] 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 peak VO2 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, the team of Dr C. Dray shown 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 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 corelated to the benefit of a chronic physical exercise in aged individuals[41].

References

  1. ↑ 1.0 1.1 1.2 Tatemoto 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. PMID 9792798.
  2. ↑ 2.0 2.1 2.2 2.3 Lee DK, Cheng R, Nguyen T, Fan T, Kariyawasam AP, Liu Y, Osmond DH, George SR, O'Dowd BF (2000). "Characterization of apelin, the ligand for the APJ receptor". J. Neurochem. 74 (1): 34–41. doi:10.1046/j.1471-4159.2000.0740034.x. PMID 10617103.
  3. ↑ 3.0 3.1 Szokodi 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. PMID 12215493.
  4. ↑ Kleinz MJ, Davenport AP (2005). "Emerging roles of apelin in biology and medicine". Pharmacol. Ther. 107 (2): 198–211. doi:10.1016/j.pharmthera.2005.04.001. PMID 15907343.
  5. ↑ 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. PMID 8294032.
  6. ↑ 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. PMID 8951791.
  7. ↑ Audigier Y (2006-04-07). "Apelin Receptor". UCSD-Nature Molecule Pages. Nature Publishing Group. doi:10.1038/mp.a000304.01. Retrieved 2009-09-02.
  8. ↑ 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. PMID 20857448.
  9. ↑ 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. PMID 21939284.
  10. ↑ 10.0 10.1 Devic 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. PMID 10473142.
  11. ↑ 11.0 11.1 11.2 Saint-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. PMID 11744380.
  12. ↑ 12.0 12.1 Masri 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. PMID 15385434.
  13. ↑ 13.0 13.1 Kasai 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. PMID 15530405.
  14. ↑ 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. PMID 16750822.
  15. ↑ 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. PMID 11384769.
  16. ↑ 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. PMID 15087458.
  17. ↑ 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. PMID 11779205.
  18. ↑ 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. PMID 18599802.
  19. ↑ 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. PMID 17336906.
  20. ↑ 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. PMID 17336905.
  21. ↑ 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. PMID 15364861.
  22. ↑ 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 (January 2005). "The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo". Cardiovasc. Res. 65 (1): 73–82. doi:10.1016/j.cardiores.2004.08.018. PMC 2517138. PMID 15621035.
  23. ↑ 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. PMID 17673668.
  24. ↑ 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. PMID 18816630.
  25. ↑ 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.
  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. ↑ 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. PMID 11004481.
  28. ↑ De Mota et al., 2000
  29. ↑ 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. PMID 11146423.
  30. ↑ 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. PMID 11883945.
  31. ↑ Sunter D, Hewson AK, Dickson SL (December 2003). "Intracerebroventricular injection of apelin-13 reduces food intake in the rat". Neurosci. Lett. 353 (1): 1–4. doi:10.1016/S0304-3940(03)00351-3. PMID 14642423.
  32. ↑ O'Shea M, Hansen MJ, Tatemoto K, Morris MJ (June 2003). "Inhibitory effect of apelin-12 on nocturnal food intake in the rat". Nutr Neurosci. 6 (3): 163–7. doi:10.1080/1028415031000111273. PMID 12793520.
  33. ↑ 33.0 33.1 33.2 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 (April 2005). "Apelin, a newly identified adipokine up-regulated by insulin and obesity". Endocrinology. 146 (4): 1764–71. doi:10.1210/en.2004-1427. PMID 15677759. Retrieved 30 June 2016.
  34. ↑ 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. PMID 14670994.
  35. ↑ 35.0 35.1 Lambrecht 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. PMID 16403840.
  36. ↑ Sorhede Winzell et al., 2005
  37. ↑ Wang G, Kundu R, Han S, Qi X, Englander EW, Quertermous T, Greeley GH (August 2009). "Ontogeny of apelin and its receptor in the rodent gastrointestinal tract". Regul. Pept. 158 (1–3): 32–9. doi:10.1016/j.regpep.2009.07.016. PMC 2761510. PMID 19660504.
  38. ↑ Sörhede Winzell M, Magnusson C, Ahrén B (November 2005). "The apj receptor is expressed in pancreatic islets and its ligand, apelin, inhibits insulin secretion in mice". Regul. Pept. 131 (1–3): 12–7. doi:10.1016/j.regpep.2005.05.004. PMID 15970338.
  39. ↑ 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. PMID 19046574.
  40. ↑ 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. 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; Pereira, Ophélie; Karaz, Sonia; Lee, Umi; Camus, Mylène; Chaoui, Karima; Mouisel, Etienne; Bigot, Anne; Mouly, Vincent; Vigneau, Mathieu; Pagano, Allan; Chopard, Angèle; Pillard, Fabien; Guyonnet, Sophie; Cesari, Matteo; Burlet, Odile; Pahor, Marco; Feige, Jerome; Vellas, Bruno; Valet, Philippe; Dray, Cedric (30 July 2018). "The exerkine apelin reverses age-associated sarcopenia". Nature Medicine. doi:10.1038/s41591-018-0131-6. PMID 30061698.

Further reading

  • 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. PMID 16530855.
  • 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. PMID 15486224.
  • 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. PMID 14645236.
  • 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. PMID 8294032.
  • 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 (October 2008). "Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis". The Journal of Clinical Investigation. 118 (10): 3343–54. doi:10.1172/JCI34871. PMC 2525695. PMID 18769630.
  • Barnes G, Japp AG, Newby DE (July 2010). "Translational promise of the apelin--APJ system". Heart. 96 (13): 1011–6. doi:10.1136/hrt.2009.191122. PMID 20584856.

External links

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