Wikipedia

Apelin

Apelin(also known asAPLN) is a peptide that in humans is encoded by theAPLNgene.[5]Apelin is one of two endogenousligandsfor theG-protein-coupledAPJ receptor[6][7][8][9][10]that is expressed at the surface of some cell types.[11]It is widely expressed in various organs such as the heart, lung, kidney, liver,adipose tissue,gastrointestinal tract,brain, adrenal glands,endothelium,and humanplasma.

APLN
Identifiers
AliasesAPLN,APEL, XNPEP2, apelin
External IDsOMIM:300297;MGI:1353624;HomoloGene:8498;GeneCards:APLN;OMA:APLN - orthologs
Orthologs
SpeciesHumanMouse
Entrez

8862

30878

Ensembl

ENSG00000171388

ENSMUSG00000037010

UniProt

Q9ULZ1

Q9R0R4

RefSeq (mRNA)

NM_017413

NM_013912

RefSeq (protein)

NP_059109

NP_038940

Location (UCSC)Chr X: 129.65 – 129.65 MbChr X: 47.11 – 47.12 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

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Apelin is a peptide hormone that was identified in 1998 by Masahiko Fujino and his colleagues atGunma UniversityandTakeda Pharmaceutical Company.[5]In 2013, a second peptide hormone namedElabelawas found byBruno Reversadeto also act as an endogenousligandto theAPLNR.

Biosynthesis

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The apelin gene encodes a pre-proprotein of 77 amino acids,[5]with asignal peptidein theN-terminalregion. After translocation into theendoplasmic reticulumand 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.[12]Recently, 46 different apelin peptides ranging from apelin 55 (proapelin) to apelin 12 have been identified in bovinecolostrum,including C-ter truncated isoforms.[13]

Physiological functions

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

Vascular

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Vascular expression of thereceptor[14][15]participates in the control ofblood pressure[6]and its activation promotes the formation of new blood vessels (angiogenesis).[15][16][17][18]The blood pressure-lowering (hypotensive) effect of apelin results from the activation of receptors expressed at the surface ofendothelial cells.[14][15]This activation induces the release ofnitric oxide(NO),[19]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[20]have suggested the existence of a balance betweenangiotensin IIsignalling (which increases blood pressure)e and apelin signalling (which lowers it). Theangiogenicactivity is the consequence of apelin action on the proliferation and migration of the endothelial cells. Apelin activatessignal transductioncascades inside the cell, includingextracellular signal-regulated kinases(ERKs),protein kinase B(PKB, also known as Akt), and p70s6 kinasephosphorylation,[16][21]which lead to the proliferation of endothelial cells and the formation of new blood vessels.[17]Genetic knockoutof the apelin gene is associated with a delay in the development of the retinal vasculature.[22]

Cardiac

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The apelin receptor is expressed early during theembryonic developmentof the heart, where it regulates the migration of cell progenitors fated to differentiate intocardiomyocytes,the contractile cells of the heart.[23][24]Its expression is also detected in the cardiomyocytes of the adult where apelin behaves as one of the most potent stimulator of cardiac contractility.[7][25][26]Aged apelin knockout mice develop progressive impairment of cardiac contractility.[27]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 cardiaccontractilityyet 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 withchronic liver disease.[28]

Exercise

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The plasma concentration of apelin is shown to increase during exercise.[29]Paradoxically, exogenous apelin in healthy volunteers reduced VO2 peak (peak oxygen consumption) in an endurance test.[30]

Brain

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Apelin receptor is also expressed in the neurons of brain areas involved in regulating water and food intake.[6][31][32]Apelin injection increases water intake[6]and apelin decreases thehypothalamicsecretion of theantidiuretichormonevasopressin.[32]Thisdiureticeffect 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.[33][34][35]

Adipose tissue

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Apelin is expressed and secreted byadipocytes,and its production is increased during adipocyte differentiation and is stimulated byinsulin.[36]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.[36]

Digestive

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Apelin receptor is expressed in several cell types of thegastro-intestinal tract:stomachenterochromaffine-like cells;[37][38]unknown cells of endocrinepancreas,[39]colonepithelial cells.[40] In stomach, activation of receptors on enterochromaffine-like cells by apelin secreted byparietal cellscan inhibit histamine release by enterochromaffine-like cells, which in turn decreases acid secretion by parietal cells.[38]In pancreas, apelin inhibits the insulin secretion induced by glucose.[39]This inhibition reveals the functional interdependency between apelin signalling and insulin signalling observed at the adipocyte level where insulin stimulate apelin production.[36]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 levelsglycemia.[41]

Bone

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Receptor expression is also observed at the surface of osteoblasts, the cell progenitors involved in bone formation.[42]

Muscle aging

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Muscle apelin expression decreases with age in rodents and humans.[43]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.[43]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.[43]Moreover, apelin receptor is also present onmuscle stem cellsand promotesin vitroandin vivocellular proliferationanddifferentiationof these cells into mature muscle cells that participate inmuscle 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.[43]

In late 2022, thelongevity therapeuticscompany BioAge announced that its licensed, orally-available apelin receptor agonist BGE-105 had greatly decreased muscle loss and sustained muscle quality andmuscle protein synthesisduring 10 days of bed rest in healthy volunteers aged 65 or older participating in adouble-blind,placebo-controlledPhase 1b trial.[44]They plan to proceed to a Phase 2 trial in older patients who are onventilatorsin theintensive care unit(ICU). Such patients suffer bothdiaphragm atrophy(the weakening of the muscles that allow one to inhale and exhale, which atrophy dangerously due to disuse during time on a ventilator[45][46][47]) andcritical 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.[44]

References

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  2. ^abcGRCm38: Ensembl release 89: ENSMUSG00000037010–Ensembl,May 2017
  3. ^"Human PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:".National Center for Biotechnology Information, U.S. National Library of Medicine.
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  7. ^abSzokodi I, Tavi P, Földes G, Voutilainen-Myllylä S, Ilves M, Tokola H, et al. (September 2002)."Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility".Circulation Research.91(5): 434–440.doi:10.1161/01.RES.0000033522.37861.69.PMID12215493.
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  25. ^Berry MF, Pirolli TJ, Jayasankar V, Burdick J, Morine KJ, Gardner TJ, et al. (September 2004)."Apelin has in vivo inotropic effects on normal and failing hearts".Circulation.110(11 Suppl 1): II187–II193.doi:10.1161/01.CIR.0000138382.57325.5c.PMID15364861.
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Further reading

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