Generic placeholder image

Current Molecular Pharmacology


ISSN (Print): 1874-4672
ISSN (Online): 1874-4702

Review Article

Apelin/Apelin Receptor System: Molecular Characteristics, Physiological Roles, and Prospects as a Target for Disease Prevention and Pharmacotherapy

Author(s): Toshihiko Kinjo, Hiroshi Higashi, Kyosuke Uno and Nobuyuki Kuramoto*

Volume 14, Issue 2, 2021

Published on: 02 June, 2020

Page: [210 - 219] Pages: 10

DOI: 10.2174/1874467213666200602133032

Price: $65


Among the various orphan G protein-coupled receptors, apelin receptor (APJ), originally identified in the human genome as an orphan G-protein-coupled receptor, was deorphanised in 1998 with the discovery of its endogenous ligand, apelin. Apelin and APJ mRNA are widely expressed in peripheral tissues and the central nervous system in mammals.

In this review, we discuss the characteristics, pharmacology, physiology, and pathology of the apelin/APJ system in mammals.

Several physiological roles of the apelin/APJ system have been reported, including in homeostasis, cardiovascular maintenance, angiogenesis, and neuroprotection. In cellular signaling, apelin has been shown to drive the PI3K/Akt, MAPK, and PKA signaling pathways, leading to cell proliferation and protection from excitotoxicity. Apelin is also found in breast milk; therefore, apelin is believed to contribute to the establishment of the infant immune system. Furthermore, activation of the apelin/APJ system is reported to restore muscular weakness associated with aging. Thus, the apelin/APJ system represents a novel target for the prevention of several important cardiovascular and neurodegenerative diseases and the maintenance of health during old age.

Keywords: Apelin/APJ system, prophylactic treatment, health promotion, GPCR, cell signaling, cell protection.

Graphical Abstract
O’Malley, B.W. Did eucaryotic steroid receptors evolve from intracrine gene regulators? Endocrinology, 1989, 125(3), 1119-1120.
[] [PMID: 2759020]
Abel, J.J. Crystalline Insulin. Proc. Natl. Acad. Sci. USA, 1926, 12(2), 132-136.
[] [PMID: 16587069]
Kawakita, M.; Ogawa, M.; Goldwasser, E.; Miyake, T. Characterization of human megakaryocyte colony-stimulating factor in the urinary extracts from patients with aplastic anemia and idiopathic thrombocytopenic purpura. Blood, 1983, 61(3), 556-560.
[] [PMID: 6600633]
Malandrino, M.; Smith, R.J. Synthesis; Secretion, and Transport of Peptide Hormones. Principles of Endocrinology and Hormone Action, Springer Nature: Switzerland, 2018.
Yi, J.; Warunek, D.; Craft, D. Degradation and Stabilization of Peptide Hormones in Human Blood Specimens. PLoS One, 2015, 10(7)e0134427
[] [PMID: 26222180]
Read, C.; Nyimanu, D.; Williams, T.L.; Huggins, D.J.; Sulentic, P.; Macrae, R.G.C.; Yang, P.; Glen, R.C.; Maguire, J.J.; Davenport, A.P. International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand. Pharmacol. Rev., 2019, 71(4), 467-502.
[] [PMID: 31492821]
O’Dowd, B.F.; Heiber, M.; Chan, A.; Heng, H.H.; Tsui, L.C.; Kennedy, J.L.; Shi, X.; Petronis, A.; George, S.R.; Nguyen, T. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene, 1993, 136(1-2), 355-360.
[] [PMID: 8294032]
Tatemoto, K.; Hosoya, M.; Habata, Y.; Fujii, R.; Kakegawa, T.; Zou, M.X.; Kawamata, Y.; Fukusumi, S.; Hinuma, S.; Kitada, C.; Kurokawa, T.; Onda, H.; Fujino, M. Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor. Biochem. Biophys. Res. Commun., 1998, 251(2), 471-476.
[] [PMID: 9792798]
Habata, Y.; Fujii, R.; Hosoya, M.; Fukusumi, S.; Kawamata, Y.; Hinuma, S.; Kitada, C.; Nishizawa, N.; Murosaki, S.; Kurokawa, T.; Onda, H.; Tatemoto, K.; Fujino, M. Apelin, the natural ligand of the orphan receptor APJ, is abundantly secreted in the colostrum. Biochim. Biophys. Acta, 1999, 1452(1), 25-35.
[] [PMID: 10525157]
Chen, X.; Bai, B.; Tian, Y.; Du, H.; Chen, J. Identification of serine 348 on the apelin receptor as a novel regulatory phosphorylation site in apelin-13-induced G protein-independent biased signaling. J. Biol. Chem., 2014, 289(45), 31173-31187.
[] [PMID: 25271156]
Alexandrov, A.I.; Mileni, M.; Chien, E.Y.; Hanson, M.A.; Stevens, R.C. Microscale fluorescent thermal stability assay for membrane proteins. Structure, 2008, 16(3), 351-359.
[] [PMID: 18334210]
Jura, N.; Scotto-Lavino, E.; Sobczyk, A.; Bar-Sagi, D. Differential modification of Ras proteins by ubiquitination. Mol. Cell, 2006, 21(5), 679-687.
[] [PMID: 16507365]
Puffer, B.A.; Sharron, M.; Coughlan, C.M.; Baribaud, F.; McManus, C.M.; Lee, B.; David, J.; Price, K.; Horuk, R.; Tsang, M.; Doms, R.W. Expression and coreceptor function of APJ for primate immunodeficiency viruses. Virology, 2000, 276(2), 435-444.
[] [PMID: 11040134]
Vickers, C.; Hales, P.; Kaushik, V.; Dick, L.; Gavin, J.; Tang, J.; Godbout, K.; Parsons, T.; Baronas, E.; Hsieh, F.; Acton, S.; Patane, M.; Nichols, A.; Tummino, P. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J. Biol. Chem., 2002, 277(17), 14838-14843.
[] [PMID: 11815627]
Japp, A.G.; Cruden, N.L.; Barnes, G.; van Gemeren, N.; Mathews, J.; Adamson, J.; Johnston, N.R.; Denvir, M.A.; Megson, I.L.; Flapan, A.D.; Newby, D.E. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation, 2010, 121(16), 1818-1827.
[] [PMID: 20385929]
Japp, A.G.; Cruden, N.L.; Amer, D.A.; Li, V.K.; Goudie, E.B.; Johnston, N.R.; Sharma, S.; Neilson, I.; Webb, D.J.; Megson, I.L.; Flapan, A.D.; Newby, D.E. Vascular effects of apelin in vivo in man. J. Am. Coll. Cardiol., 2008, 52(11), 908-913.
[] [PMID: 18772060]
Chen, M.M.; Ashley, E.A.; Deng, D.X.; Tsalenko, A.; Deng, A.; Tabibiazar, R.; Ben-Dor, A.; Fenster, B.; Yang, E.; King, J.Y.; Fowler, M.; Robbins, R.; Johnson, F.L.; Bruhn, L.; McDonagh, T.; Dargie, H.; Yakhini, Z.; Tsao, P.S.; Quertermous, T. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation, 2003, 108(12), 1432-1439.
[] [PMID: 12963638]
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, J.S.; Valet, P. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology, 2005, 146(4), 1764-1771.
[] [PMID: 15677759]
Macaluso, N.J.; Pitkin, S.L.; Maguire, J.J.; Davenport, A.P.; Glen, R.C. Discovery of a competitive apelin receptor (APJ) antagonist. ChemMedChem, 2011, 6(6), 1017-1023.
[] [PMID: 21560248]
Brame, A.L.; Maguire, J.J.; Yang, P.; Dyson, A.; Torella, R.; Cheriyan, J.; Singer, M.; Glen, R.C.; Wilkinson, I.B.; Davenport, A.P. Design, characterization, and first-in-human study of the vascular actions of a novel biased apelin receptor agonist. Hypertension, 2015, 65(4), 834-840.
[] [PMID: 25712721]
Iturrioz, X.; Alvear-Perez, R.; De Mota, N.; Franchet, C.; Guillier, F.; Leroux, V.; Dabire, H.; Le Jouan, M.; Chabane, H.; Gerbier, R.; Bonnet, D.; Berdeaux, A.; Maigret, B.; Galzi, J.L.; Hibert, M.; Llorens-Cortes, C. Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist. FASEB J., 2010, 24(5), 1506-1517.
[] [PMID: 20040517]
Khan, P.; Maloney, P.R.; Hedrick, M.; Gosalia, P.; Milewski, M.; Li, L.; Roth, G.P.; Sergienko, E.; Suyama, E.; Sugarman, E.; Nguyen, K.; Mehta, A.; Vasile, S.; Su, Y.; Shi, S.; Stonich, D.; Nguyen, H.; Zeng, F.Y.; Novo, A.M.; Vicchiarelli, M.; Diwan, J.; Chung, T.D.Y.; Pinkerton, A.B.; Smith, L.H. Functional Agonists of the Apelin (APJ); Receptor. Probe Reports from the NIH Molecular Libraries Program, 2011.
Maloney, P.R.; Khan, P.; Hedrick, M.; Gosalia, P.; Milewski, M.; Li, L.; Roth, G.P.; Sergienko, E.; Suyama, E.; Sugarman, E.; Nguyen, K.; Mehta, A.; Vasile, S.; Su, Y.; Stonich, D.; Nguyen, H.; Zeng, F.Y.; Novo, A.M.; Vicchiarelli, M.; Diwan, J.; Chung, T.D.; Smith, L.H.; Pinkerton, A.B. Discovery of 4-oxo-6-((pyrimidin-2-ylthio)methyl)-4H-pyran-3-yl 4-nitrobenzoate (ML221) as a functional antagonist of the apelin (APJ) receptor. Bioorg. Med. Chem. Lett., 2012, 22(21), 6656-6660.
[] [PMID: 23010269]
Ho, L.; Tan, S.Y.; Wee, S.; Wu, Y.; Tan, S.J.; Ramakrishna, N.B.; Chng, S.C.; Nama, S.; Szczerbinska, I.; Chan, Y.S.; Avery, S.; Tsuneyoshi, N.; Ng, H.H.; Gunaratne, J.; Dunn, N.R.; Reversade, B. ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway. Cell Stem Cell, 2015, 17(4), 435-447.
[] [PMID: 26387754]
Pope, G.R.; Roberts, E.M.; Lolait, S.J.; O’Carroll, A.M. Central and peripheral apelin receptor distribution in the mouse: species differences with rat. Peptides, 2012, 33(1), 139-148.
[] [PMID: 22197493]
Medhurst, A.D.; Jennings, C.A.; Robbins, M.J.; Davis, R.P.; Ellis, C.; Winborn, K.Y.; Lawrie, K.W.; Hervieu, G.; Riley, G.; Bolaky, J.E.; Herrity, N.C.; Murdock, P.; Darker, J.G. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J. Neurochem., 2003, 84(5), 1162-1172.
[] [PMID: 12603839]
Choe, W.; Albright, A.; Sulcove, J.; Jaffer, S.; Hesselgesser, J.; Lavi, E.; Crino, P.; Kolson, D.L. Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells. J. Neurovirol., 2000, 6(Suppl. 1), S61-S69.
[PMID: 10871767]
Han, S.; Englander, E.W.; Gomez, G.A.; Aronson, J.F.; Rastellini, C.; Garofalo, R.P.; Kolli, D.; Quertermous, T.; Kundu, R.; Greeley, G.H., Jr Pancreatitis activates pancreatic apelin-APJ axis in mice. Am. J. Physiol. Gastrointest. Liver Physiol., 2013, 305(2), G139-G150.
[] [PMID: 23681476]
Ishimaru, Y.; Shibagaki, F.; Yamamuro, A.; Yoshioka, Y.; Maeda, S. An apelin receptor antagonist prevents pathological retinal angiogenesis with ischemic retinopathy in mice. Sci. Rep., 2017, 7(1), 15062.
[] [PMID: 29118394]
Wang, G.; Kundu, R.; Han, S.; Qi, X.; Englander, E.W.; Quertermous, T.; Greeley, G.H., Jr Ontogeny of apelin and its receptor in the rodent gastrointestinal tract. Regul. Pept., 2009, 158(1-3), 32-39.
[] [PMID: 19660504]
Fournel, A.; Drougard, A.; Duparc, T.; Marlin, A.; Brierley, S.M.; Castro, J.; Le-Gonidec, S.; Masri, B.; Colom, A.; Lucas, A.; Rousset, P.; Cenac, N.; Vergnolle, N.; Valet, P.; Cani, P.D.; Knauf, C. Apelin targets gut contraction to control glucose metabolism via the brain. Gut, 2017, 66(2), 258-269.
[] [PMID: 26565000]
Noguchi, S.; Arakawa, T.; Fukuda, S.; Furuno, M.; Hasegawa, A.; Hori, F.; Ishikawa-Kato, S.; Kaida, K.; Kaiho, A.; Kanamori-Katayama, M.; Kawashima, T.; Kojima, M.; Kubosaki, A.; Manabe, R.I.; Murata, M.; Nagao-Sato, S.; Nakazato, K.; Ninomiya, N.; Nishiyori-Sueki, H.; Noma, S.; Saijyo, E.; Saka, A.; Sakai, M.; Simon, C.; Suzuki, N.; Tagami, M.; Watanabe, S.; Yoshida, S.; Arner, P.; Axton, R.A.; Babina, M.; Baillie, J.K.; Barnett, T.C.; Beckhouse, A.G.; Blumenthal, A.; Bodega, B.; Bonetti, A.; Briggs, J.; Brombacher, F.; Carlisle, A.J.; Clevers, H.C.; Davis, C.A.; Detmar, M.; Dohi, T.; Edge, A.S.B.; Edinger, M.; Ehrlund, A.; Ekwall, K.; Endoh, M.; Enomoto, H.; Eslami, A.; Fagiolini, M.; Fairbairn, L.; Farach-Carson, M.C.; Faulkner, G.J.; Ferrai, C.; Fisher, M.E.; Forrester, L.M.; Fujita, R.; Furusawa, J.I.; Geijtenbeek, T.B.; Gingeras, T.; Goldowitz, D.; Guhl, S.; Guler, R.; Gustincich, S.; Ha, T.J.; Hamaguchi, M.; Hara, M.; Hasegawa, Y.; Herlyn, M.; Heutink, P.; Hitchens, K.J.; Hume, D.A.; Ikawa, T.; Ishizu, Y.; Kai, C.; Kawamoto, H.; Kawamura, Y.I.; Kempfle, J.S.; Kenna, T.J.; Kere, J.; Khachigian, L.M.; Kitamura, T.; Klein, S.; Klinken, S.P.; Knox, A.J.; Kojima, S.; Koseki, H.; Koyasu, S.; Lee, W.; Lennartsson, A.; Mackay-Sim, A.; Mejhert, N.; Mizuno, Y.; Morikawa, H.; Morimoto, M.; Moro, K.; Morris, K.J.; Motohashi, H.; Mummery, C.L.; Nakachi, Y.; Nakahara, F.; Nakamura, T.; Nakamura, Y.; Nozaki, T.; Ogishima, S.; Ohkura, N.; Ohno, H.; Ohshima, M.; Okada-Hatakeyama, M.; Okazaki, Y.; Orlando, V.; Ovchinnikov, D.A.; Passier, R.; Patrikakis, M.; Pombo, A.; Pradhan-Bhatt, S.; Qin, X.Y.; Rehli, M.; Rizzu, P.; Roy, S.; Sajantila, A.; Sakaguchi, S.; Sato, H.; Satoh, H.; Savvi, S.; Saxena, A.; Schmidl, C.; Schneider, C.; Schulze-Tanzil, G.G.; Schwegmann, A.; Sheng, G.; Shin, J.W.; Sugiyama, D.; Sugiyama, T.; Summers, K.M.; Takahashi, N.; Takai, J.; Tanaka, H.; Tatsukawa, H.; Tomoiu, A.; Toyoda, H.; van de Wetering, M.; van den Berg, L.M.; Verardo, R.; Vijayan, D.; Wells, C.A.; Winteringham, L.N.; Wolvetang, E.; Yamaguchi, Y.; Yamamoto, M.; Yanagi-Mizuochi, C.; Yoneda, M.; Yonekura, Y.; Zhang, P.G.; Zucchelli, S.; Abugessaisa, I.; Arner, E.; Harshbarger, J.; Kondo, A.; Lassmann, T.; Lizio, M.; Sahin, S.; Sengstag, T.; Severin, J.; Shimoji, H.; Suzuki, M.; Suzuki, H.; Kawai, J.; Kondo, N.; Itoh, M.; Daub, C.O.; Kasukawa, T.; Kawaji, H.; Carninci, P.; Forrest, A.R.R.; Hayashizaki, Y. FANTOM5 CAGE profiles of human and mouse samples. Sci. Data, 2017, 4170112
[] [PMID: 28850106]
Hosoya, M.; Kawamata, Y.; Fukusumi, S.; Fujii, R.; Habata, Y.; Hinuma, S.; Kitada, C.; Honda, S.; Kurokawa, T.; Onda, H.; Nishimura, O.; Fujino, M. Molecular and functional characteristics of APJ. Tissue distribution of mRNA and interaction with the endogenous ligand apelin. J. Biol. Chem., 2000, 275(28), 21061-21067.
[] [PMID: 10777510]
Martelli, A.M.; Nyåkern, M.; Tabellini, G.; Bortul, R.; Tazzari, P.L.; Evangelisti, C.; Cocco, L. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia, 2006, 20(6), 911-928.
[] [PMID: 16642045]
Zhang, Z.; Yu, B.; Tao, G.Z. Apelin protects against cardiomyocyte apoptosis induced by glucose deprivation. Chin. Med. J. (Engl.), 2009, 122(19), 2360-2365.
[PMID: 20079140]
Nagano, K.; Ishida, J.; Unno, M.; Matsukura, T.; Fukamizu, A. Apelin elevates blood pressure in ICR mice with L‑NAME‑induced endothelial dysfunction. Mol. Med. Rep., 2013, 7(5), 1371-1375.
[] [PMID: 23525196]
Siddiquee, K.; Hampton, J.; McAnally, D.; May, L.; Smith, L. The apelin receptor inhibits the angiotensin II type 1 receptor via allosteric trans-inhibition. Br. J. Pharmacol., 2013, 168(5), 1104-1117.
[] [PMID: 22935142]
Edinger, A.L.; Hoffman, T.L.; Sharron, M.; Lee, B.; Yi, Y.; Choe, W.; Kolson, D.L.; Mitrovic, B.; Zhou, Y.; Faulds, D.; Collman, R.G.; Hesselgesser, J.; Horuk, R.; Doms, R.W. An orphan seven-transmembrane domain receptor expressed widely in the brain functions as a coreceptor for human immunodeficiency virus type 1 and simian immunodeficiency virus. J. Virol., 1998, 72(10), 7934-7940.
[] [PMID: 9733831]
Zhang, Q.; Yao, F.; Raizada, M.K.; O’Rourke, S.T.; Sun, C. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ. Res., 2009, 104(12), 1421-1428.
[] [PMID: 19443838]
Wang, W.; McKinnie, S.M.; Patel, V.B.; Haddad, G.; Wang, Z.; Zhabyeyev, P.; Das, S.K.; Basu, R.; McLean, B.; Kandalam, V.; Penninger, J.M.; Kassiri, Z.; Vederas, J.C.; Murray, A.G.; Oudit, G.Y. Loss of Apelin exacerbates myocardial infarction adverse remodeling and ischemia-reperfusion injury: therapeutic potential of synthetic Apelin analogues. J. Am. Heart Assoc., 2013, 2(4)e000249
[] [PMID: 23817469]
Tatemoto, K.; Takayama, K.; Zou, M.X.; Kumaki, I.; Zhang, W.; Kumano, K.; Fujimiya, M. The novel peptide apelin lowers blood pressure via a nitric oxide-dependent mechanism. Regul. Pept., 2001, 99(2-3), 87-92.
[] [PMID: 11384769]
Charo, D.N.; Ho, M.; Fajardo, G.; Kawana, M.; Kundu, R.K.; Sheikh, A.Y.; Finsterbach, T.P.; Leeper, N.J.; Ernst, K.V.; Chen, M.M.; Ho, Y.D.; Chun, H.J.; Bernstein, D.; Ashley, E.A.; Quertermous, T. Endogenous regulation of cardiovascular function by apelin-APJ. Am. J. Physiol. Heart Circ. Physiol., 2009, 297(5), H1904-H1913.
[] [PMID: 19767528]
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, G.G.; Komnenovic, V.; Kolm, U.; Metzler, B.; Ricci, R.; Hara, H.; Meixner, A.; Nghiem, M.; Chen, X.; Dawood, F.; Wong, K.M.; Sarao, R.; Cukerman, E.; Kimura, A.; Hein, L.; Thalhammer, J.; Liu, P.P.; Penninger, J.M. Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload. Circ. Res., 2007, 101(4), e32-e42.
[] [PMID: 17673668]
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. Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo. J. Biol. Chem., 2004, 279(25), 26274-26279.
[] [PMID: 15087458]
Dray, C.; Knauf, C.; Daviaud, D.; Waget, A.; Boucher, J.; Buléon, M.; Cani, P.D.; Attané, C.; Guigné, C.; Carpéné, C.; Burcelin, R.; Castan-Laurell, I.; Valet, P. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab., 2008, 8(5), 437-445.
[] [PMID: 19046574]
Yue, P.; Jin, H.; Aillaud, M.; Deng, A.C.; Azuma, J.; Asagami, T.; Kundu, R.K.; Reaven, G.M.; Quertermous, T.; Tsao, P.S. Apelin is necessary for the maintenance of insulin sensitivity. Am. J. Physiol. Endocrinol. Metab., 2010, 298(1), E59-E67.
[] [PMID: 19861585]
Li, L.; Yang, G.; Li, Q.; Tang, Y.; Yang, M.; Yang, H.; Li, K. Changes and relations of circulating visfatin, apelin, and resistin levels in normal, impaired glucose tolerance, and type 2 diabetic subjects. Exp. Clin. Endocrinol. Diabetes, 2006, 114(10), 544-548.
[] [PMID: 17177135]
Kälin, R.E.; Kretz, M.P.; Meyer, A.M.; Kispert, A.; Heppner, F.L.; Brändli, A.W. Paracrine and autocrine mechanisms of apelin signaling govern embryonic and tumor angiogenesis. Dev. Biol., 2007, 305(2), 599-614.
[] [PMID: 17412318]
Masri, B.; Morin, N.; Cornu, M.; Knibiehler, B.; Audigier, Y. Apelin (65-77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB J., 2004, 18(15), 1909-1911.
[] [PMID: 15385434]
Kidoya, H.; Ueno, M.; Yamada, Y.; Mochizuki, N.; Nakata, M.; Yano, T.; Fujii, R.; Takakura, N. Spatial and temporal role of the apelin/APJ system in the caliber size regulation of blood vessels during angiogenesis. EMBO J., 2008, 27(3), 522-534.
[] [PMID: 18200044]
Kasai, A.; Shintani, N.; Kato, H.; Matsuda, S.; Gomi, F.; Haba, R.; Hashimoto, H.; Kakuda, M.; Tano, Y.; Baba, A. Retardation of retinal vascular development in apelin-deficient mice. Arterioscler. Thromb. Vasc. Biol., 2008, 28(10), 1717-1722.
[] [PMID: 18599802]
Kasai, A.; Ishimaru, Y.; Kinjo, T.; Satooka, T.; Matsumoto, N.; Yoshioka, Y.; Yamamuro, A.; Gomi, F.; Shintani, N.; Baba, A.; Maeda, S. Apelin is a crucial factor for hypoxia-induced retinal angiogenesis. Arterioscler. Thromb. Vasc. Biol., 2010, 30(11), 2182-2187.
[] [PMID: 20705920]
McKenzie, J.A.; Fruttiger, M.; Abraham, S.; Lange, C.A.; Stone, J.; Gandhi, P.; Wang, X.; Bainbridge, J.; Moss, S.E.; Greenwood, J. Apelin is required for non-neovascular remodeling in the retina. Am. J. Pathol., 2012, 180(1), 399-409.
[] [PMID: 22067912]
O’Donnell, L.A.; Agrawal, A.; Sabnekar, P.; Dichter, M.A.; Lynch, D.R.; Kolson, D.L. Apelin, an endogenous neuronal peptide, protects hippocampal neurons against excitotoxic injury. J. Neurochem., 2007, 102(6), 1905-1917.
[] [PMID: 17767704]
Kalantaripour, T.P.; Esmaeili-Mahani, S.; Sheibani, V.; Najafipour, H.; Asadi-Shekaari M, M. Apelin-13 protects rat primary cortical glia-neuron co-culture against pentylenetetrazole-induced toxicity. Biomed. Pharmacother., 2017, 87, 661-668.
[] [PMID: 28088732]
Bao, H.J.; Qiu, H.Y.; Kuai, J.X.; Song, C.J.; Wang, S.X.; Wang, C.Q.; Peng, H.B.; Han, W.C.; Wu, Y.P. Apelin-13 as a novel target for intervention in secondary injury after traumatic brain injury. Neural Regen. Res., 2016, 11(7), 1128-1133.
[] [PMID: 27630697]
Bao, H.; Yang, X.; Huang, Y.; Qiu, H.; Huang, G.; Xiao, H.; Kuai, J. The neuroprotective effect of apelin-13 in a mouse model of intracerebral hemorrhage. Neurosci. Lett., 2016, 628, 219-224.
[] [PMID: 27343409]
Kasai, A.; Kinjo, T.; Ishihara, R.; Sakai, I.; Ishimaru, Y.; Yoshioka, Y.; Yamamuro, A.; Ishige, K.; Ito, Y.; Maeda, S. Apelin deficiency accelerates the progression of amyotrophic lateral sclerosis. PLoS One, 2011, 6(8)e23968
[] [PMID: 21887354]
Han, S.; Englander, E.W.; Gomez, G.A.; Greeley, G.H., Jr Apelin Regulates Nuclear Factor-κB’s Involvement in the Inflammatory Response of Pancreatitis. Pancreas, 2017, 46(1), 64-70.
[] [PMID: 27846147]
Luo, H.; Xiang, Y.; Qu, X.; Liu, H.; Liu, C.; Li, G.; Han, L.; Qin, X. Apelin-13 Suppresses Neuroinflammation Against Cognitive Deficit in a Streptozotocin-Induced Rat Model of Alzheimer’s Disease Through Activation of BDNF-TrkB Signaling Pathway. Front. Pharmacol., 2019, 10, 395.
[] [PMID: 31040784]
Mesmin, C.; Fenaille, F.; Becher, F.; Tabet, J.C.; Ezan, E. Identification and characterization of apelin peptides in bovine colostrum and milk by liquid chromatography-mass spectrometry. J. Proteome Res., 2011, 10(11), 5222-5231.
[] [PMID: 21939284]
Shin, K.; Chapman, N.A.; Sarker, M.; Kenward, C.; Huang, S.K.; Weatherbee-Martin, N.; Pandey, A.; Dupré, D.J.; Rainey, J.K. Bioactivity of the putative apelin proprotein expands the repertoire of apelin receptor ligands. Biochim. Biophys. Acta, Gen. Subj., 2017, 1861(8), 1901-1912.
[] [PMID: 28546009]
Murata, K.; Ishida, J.; Ishimaru, T.; Mizukami, H.; Hamada, J.; Saito, C.; Fukamizu, A. Lactation Is a Risk Factor of Postpartum Heart Failure in Mice with Cardiomyocyte-specific Apelin Receptor (APJ) Overexpression. J. Biol. Chem., 2016, 291(21), 11241-11251.
[] [PMID: 27033703]
Sawane, M.; Kajiya, K.; Kidoya, H.; Takagi, M.; Muramatsu, F.; Takakura, N. Apelin inhibits diet-induced obesity by enhancing lymphatic and blood vessel integrity. Diabetes, 2013, 62(6), 1970-1980.
[] [PMID: 23378608]
Kim, J.D.; Kang, Y.; Kim, J.; Papangeli, I.; Kang, H.; Wu, J.; Park, H.; Nadelmann, E.; Rockson, S.G.; Chun, H.J.; Jin, S.W. Essential role of Apelin signaling during lymphatic development in zebrafish. Arterioscler. Thromb. Vasc. Biol., 2014, 34(2), 338-345.
[] [PMID: 24311379]
Ge, Y.; Li, Y.; Chen, Q.; Zhu, W.; Zuo, L.; Guo, Z.; Gong, J.; Cao, L.; Gu, L.; Li, J. Adipokine apelin ameliorates chronic colitis in Il-10-/- mice by promoting intestinal lymphatic functions. Biochem. Pharmacol., 2018, 148, 202-212.
[] [PMID: 29309764]
Zhu, S.; Sun, F.; Li, W.; Cao, Y.; Wang, C.; Wang, Y.; Liang, D.; Zhang, R.; Zhang, S.; Wang, H.; Cao, F. Apelin stimulates glucose uptake through the PI3K/Akt pathway and improves insulin resistance in 3T3-L1 adipocytes. Mol. Cell. Biochem., 2011, 353(1-2), 305-313.
[] [PMID: 21461612]
Zhu, J.; Dou, S.; Wang, C.; Jiang, Y.; Cheng, B.; Apelin-36 Mitigates MPTP/MPP +-induced Neurotoxicity: Involvement of α-Synuclein and Endoplasmic Reticulum Stress. Brain Res., 2019. 1721, e146334
Zhu, J.; Dou, S.; Jiang, Y.; Chen, J.; Wang, C.; Cheng, B. Apelin-13 protects dopaminergic neurons in MPTP-induced Parkinson’s disease model mice through inhibiting endoplasmic reticulum stress and promoting autophagy. Brain Res., 2019, 1715, 203-212.
[] [PMID: 30914252]
Anker, S.D.; Morley, J.E.; von Haehling, S. Welcome to the ICD-10 code for sarcopenia. J. Cachexia Sarcopenia Muscle, 2016, 7(5), 512-514.
[] [PMID: 27891296]
Vinel, C.; Lukjanenko, L.; Batut, A.; Deleruyelle, S.; Pradère, J.P.; 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, A.F.; Chopard, A.; Pillard, F.; Guyonnet, S.; Cesari, M.; Burlet-Schiltz, O.; Pahor, M.; Feige, J.N.; Vellas, B.; Valet, P.; Dray, C. The exerkine apelin reverses age-associated sarcopenia. Nat. Med., 2018, 24(9), 1360-1371.
[] [PMID: 30061698]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy