Affinage

APLN

Apelin · UniProt Q9ULZ1

Length
77 aa
Mass
8.6 kDa
Annotated
2026-06-09
100 papers in source corpus 31 papers cited in narrative 31 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Apelin (APLN) is a secreted peptide hormone, processed from a precursor into multiple bioactive forms (apelin-13, apelin-17, apelin-36), that acts as an endogenous agonist of the G-protein-coupled apelin receptor APJ/APLNR to coordinate cardiovascular, angiogenic, metabolic, and tissue-protective programs (PMID:15907343). Engagement of APJ activates Gαi2/Gαi3 by molecular rearrangement and Gαo/Gαq by classical dissociation (PMID:25193074), driving PI3K/Akt and MAPK/ERK signaling that underlies its cellular effects, including cardioprotection against ischemia-reperfusion injury via the RISK pathway and delay of mitochondrial permeability transition pore opening (PMID:17694254). Receptor activation is followed by GRK2-mediated, β-arrestin1-independent, clathrin/dynamin-dependent internalization, and downstream signaling bias is encoded structurally: the I109^3.32 residue of TM3 controls the balance between G protein and β-arrestin/GRK recruitment (PMID:30409826, PMID:27492965), and structure-guided design of G-protein-biased agonists yields improved efficacy against cardiac hypertrophy (PMID:38428423). Crystal and cryo-EM structures defined a curved two-site peptide binding mode and stoichiometry-dependent G protein coupling, and showed that the second endogenous ligand Elabela/Toddler engages APJ through a distinct binding mode from apelin (PMID:28528775, PMID:35817871, PMID:32301550). APLN is transcriptionally induced by hypoxia through HIF-1α binding to an intronic hypoxia-responsive element (PMID:18617693), by β-catenin in hepatocellular carcinoma (PMID:31410213), and by muscle contraction as an exerkine (PMID:30061698). Functionally, apelin marks and drives sprouting (tip) endothelial cells in angiogenesis (PMID:25597280), promotes lymphangiogenesis (PMID:24962866), directs cardiac precursor migration during gastrulation (PMID:17336905), enhances muscle mitochondriogenesis and autophagy (PMID:30061698), and protects vasculature against aneurysm and oxidative injury (PMID:31189595, PMID:32879139); its peptides are inactivated by ACE2 and by neutral endopeptidase (PMID:15907343, PMID:31189595). The APLN/APJ axis also regulates Sertoli-cell carnitine production and blood-testis barrier integrity (PMID:36443325) and cholangiocyte proliferation through Nox4/ROS/ERK signaling (PMID:32964473), and apelin inhibition reduces tumor angiogenesis and glioblastoma stem-like cell expansion (PMID:31267692, PMID:29053791).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2005 High

    Established that apelin peptides arise from a single gene to activate the GPCR APJ and are inactivated by ACE2, defining the core ligand-receptor-degradation axis.

    Evidence Biochemical/pharmacological characterization and review of experimental literature

    PMID:15907343

    Open questions at the time
    • Did not resolve the G protein coupling specificity downstream of APJ
    • Tissue-specific roles of distinct peptide isoforms unaddressed
  2. 2007 High

    Defined a developmental requirement for apelin/APJ signaling in directing convergence of cardiac precursors, showing the axis is not merely a metabolic/cardiovascular modulator but a morphogenetic cue.

    Evidence Zebrafish loss- and gain-of-function genetics with in situ hybridization and confocal imaging of precursor migration

    PMID:17336905

    Open questions at the time
    • Mammalian conservation of this gastrulation role not established here
    • Downstream effectors driving directional migration unidentified
  3. 2007 High

    Identified the signaling pathways for apelin cardioprotection, showing PI3K-Akt and ERK (RISK pathway) activation and MPTP delay mediate protection against ischemia-reperfusion.

    Evidence In vivo rodent I/R, Langendorff perfusion, isolated cardiomyocytes, PI3K and MEK inhibitors

    PMID:17694254

    Open questions at the time
    • Receptor-proximal coupling to PI3K/ERK not dissected
    • Did not address chronic versus acute cardiac effects
  4. 2008 High

    Resolved how apelin transcription is regulated under stress, demonstrating HIF-1α directly binds an intronic HRE to induce apelin during hypoxia and that this drives endothelial proliferation and vessel regeneration.

    Evidence ChIP, reporter assays with mutagenesis, siRNA knockdown, zebrafish fin regeneration

    PMID:18617693

    Open questions at the time
    • Other transcriptional inputs not yet mapped
    • Quantitative contribution of apelin to in vivo angiogenesis not isolated
  5. 2014 Medium

    Clarified the heterotrimeric G protein logic of APJ, showing Gαi2/Gαi3 activate by molecular rearrangement while Gαo/Gαq dissociate classically, refining how a single receptor produces diverse outputs.

    Evidence BRET/FRET in live HEK293 cells with fluorescent G-protein subunits

    PMID:25193074

    Open questions at the time
    • Single-lab live-cell assay without structural confirmation
    • Functional consequences of rearrangement versus dissociation untested
  6. 2015 High

    Demonstrated apelin specifically marks and is functionally required in sprouting (tip) endothelial cells, downstream of VEGF-VEGFR2, distinguishing active from quiescent vasculature.

    Evidence Apln-CreER lineage tracing, tumor and ischemia models, genetic ablation

    PMID:25597280

    Open questions at the time
    • Mechanism linking VEGFR2 to apelin transcription unresolved
    • Autocrine versus paracrine action on tip cells not distinguished
  7. 2015 High

    Identified Elabela/Toddler as a second endogenous APJ agonist that drives internalization, cAMP suppression, ERK activation, and angiogenesis, expanding the receptor's ligand repertoire.

    Evidence Reconstituted HEK293/CHO systems, cAMP, ERK, calcium assays, aortic ring relaxation

    PMID:25639753

    Open questions at the time
    • Relative physiological roles of apelin versus Elabela unclear
    • Tissue contexts of preferential ligand use undefined
  8. 2015 Medium

    Extended apelin/APJ signaling into adipose thermogenesis and metabolism, showing PI3K/Akt and AMPK drive browning, mitochondrial biogenesis, and oxygen consumption.

    Evidence Adipocyte differentiation assays, pathway inhibitors, mouse model, mitochondrial function assays

    PMID:25931124

    Open questions at the time
    • Single-lab finding
    • In vivo contribution to whole-body energy balance not quantified
  9. 2017 High

    Provided the first atomic-resolution view of APJ, revealing a curved two-site ligand binding mode and the residues governing apelin recognition.

    Evidence X-ray crystallography at 2.6 Å with a peptide mimetic, mutagenesis, MD simulation

    PMID:28528775

    Open questions at the time
    • Captured with a mimetic rather than native peptide
    • G-protein-bound active state not resolved in this structure
  10. 2017 High

    Identified protamine as a full APJ antagonist whose activity is reversed by heparin, providing a pharmacological tool blocking both G protein and β-arrestin signaling and abolishing apelin-mediated angiogenesis and vasodilatation.

    Evidence Binding, cAMP and β-arrestin assays, ex vivo and in vivo functional tests, heparin reversal

    PMID:28242772

    Open questions at the time
    • Specificity of protamine for APJ versus other targets not fully bounded
    • Therapeutic window not defined
  11. 2016 High

    Dissected APJ trafficking, showing apelin-induced internalization is GRK2- and dynamin/EPS15-dependent but β-arrestin1-independent, and that ERK desensitization occurs upstream of internalization.

    Evidence Dominant-negative constructs and fluorescence imaging of APJ internalization in HEK293

    PMID:27492965

    Open questions at the time
    • Single-lab dominant-negative approach
    • Role of β-arrestin2 versus β-arrestin1 not separated
  12. 2018 High

    Mapped signaling bias to a single TM3 residue, showing I109A converts APJ into a G-protein-biased receptor defective in GRK and β-arrestin recruitment, establishing a structural basis for biased agonism.

    Evidence Site-directed mutagenesis, G protein/arrestin recruitment assays, ERK assay, MD simulation

    PMID:30409826

    Open questions at the time
    • Single-lab mutagenesis
    • In vivo consequences of forced bias not tested in this study
  13. 2018 High

    Defined apelin as a contraction-induced exerkine essential for muscle homeostasis, with loss causing age-dependent dysfunction and restoration enhancing mitochondriogenesis, autophagy, and stem-cell-mediated regeneration.

    Evidence Apelin and APLNR knockout mice, replacement and exercise models, muscle stem cell and mitochondrial assays

    PMID:30061698

    Open questions at the time
    • Direct molecular targets in myofibers versus stem cells not fully separated
    • Human translatability of the aging phenotype untested
  14. 2018 High

    Linked apelin to electrophysiological stability, showing apelin deficiency raises atrial superoxide and slows conduction while apelin reduces atrial fibrillation vulnerability via increased sodium currents.

    Evidence Apelin knockout mice, optical mapping, patch-clamp sodium currents, NADPH oxidase assay

    PMID:32879139

    Open questions at the time
    • Receptor-to-sodium-channel coupling mechanism unresolved
    • Relevance to human atrial fibrillation not directly tested
  15. 2019 High

    Established apelin as a vasoprotective factor in aneurysm, identifying NEP as a degrading enzyme, showing apelin induces ACE2, and validating a NEP-resistant analog therapeutically.

    Evidence Apln knockout mice, Ang II-induced AAA, aortic SMC culture, peptide analog design, Ldlr-/- model

    PMID:31189595

    Open questions at the time
    • Balance between ACE2 induction (protective) and ACE2 degradation of apelin not fully reconciled
    • Long-term analog safety not addressed
  16. 2019 Medium

    Showed APLN is a β-catenin transcriptional target in hepatocellular carcinoma that promotes tumor proliferation through PI3K/Akt-GSK3β-cyclin D1 signaling, connecting Wnt pathway activation to apelin-driven oncogenesis.

    Evidence β-catenin ChIP at APLN promoter, ectopic expression/knockdown, Western blot, xenograft

    PMID:31410213

    Open questions at the time
    • Single-lab study
    • Autocrine versus paracrine APJ engagement in tumor not resolved
  17. 2022 High

    Captured fully active APJR-G protein complexes in both 2:1 and 1:1 stoichiometries, implicating receptor dimerization stoichiometry in shaping G protein coupling.

    Evidence Cryo-EM single-particle analysis with ELA and small-molecule ligands

    PMID:35817871

    Open questions at the time
    • Physiological prevalence of dimeric versus monomeric signaling in cells unknown
    • Functional output differences between stoichiometries not directly measured
  18. 2024 High

    Identified structural 'twin hotspots' governing G protein versus β-arrestin bias and used them to design G-protein-biased agonists with superior anti-hypertrophic efficacy, translating structural insight into improved therapeutics.

    Evidence Multiple cryo-EM structures, signaling assays, structure-based design, in vivo cardiac hypertrophy models

    PMID:38428423

    Open questions at the time
    • Long-term in vivo safety of biased agonists not established
    • Generalizability of hotspots to other peptide GPCRs untested
  19. 2020 High

    Demonstrated distinct binding determinants for the two endogenous ligands, showing Asp282/Asp284 are critical for apelin but not Elabela, mechanistically separating their receptor engagement.

    Evidence Alanine scanning of ELA, receptor mutagenesis, binding, cAMP, β-arrestin2 assays in CHO cells

    PMID:32301550

    Open questions at the time
    • Single-lab study
    • Structural basis of differential engagement not visualized here
  20. 2021 Medium

    Catalogued ligand-specific bias across apelin and Elabela isoforms, showing all engage both G protein and β-arrestin pathways but with markedly different bias ratios.

    Evidence cAMP, Ca2+, ERK, β-arrestin1/2, GRK, AP2 assays in APJ cells

    PMID:33746758

    Open questions at the time
    • Single-lab quantitative bias values
    • Physiological relevance of extreme bias ratios untested
  21. 2021 High

    Revealed a pathological APLN/APJ role in diabetic testis, where Sertoli-cell apelin suppresses carnitine production and adhesion genes to disrupt the blood-testis barrier, reversible by antagonist ML221.

    Evidence Single-cell transcriptomics of human diabetic testes, Sertoli cell culture, db/db mice, human testis culture, ML221

    PMID:36443325

    Open questions at the time
    • Direct transcriptional link between APJ signaling and adhesion gene repression not fully mapped
    • Reversibility window in human disease unknown
  22. 2021 High

    Defined apelin's profibrotic role in liver, driving cholangiocyte proliferation through Nox4/ROS/ERK and activating hepatic stellate cells via ROS, with knockout or antagonism reducing fibrosis.

    Evidence APLN knockout mice, bile duct ligation, Mdr2-/- mice, pathway inhibitors, biliary and HSC cultures

    PMID:32964473

    Open questions at the time
    • Source of apelin within injured liver not fully resolved
    • Crosstalk with other fibrogenic signals undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How tissue context selects among apelin's many divergent outputs—protective versus profibrotic versus pro-tumorigenic—and how ligand identity, receptor bias, and stoichiometry are integrated in vivo remains unresolved.
  • No unified model linking biased agonism to specific physiological versus pathological outcomes
  • Endogenous peptide isoform balance in different tissues uncharacterized
  • Predictive rules for therapeutic agonist versus antagonist choice not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 4 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1643685 Disease 5 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ACE2APLNR

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Apelin peptides are derived from a single gene and activate the 7-transmembrane G-protein-coupled receptor APJ; apelin peptides also represent substrates for ACE2 carboxypeptidase, which cleaves and inactivates them. Biochemical/pharmacological characterization; review of experimental literature Pharmacology & therapeutics High 15907343
2008 Hypoxia induces apelin expression in endothelial and vascular smooth muscle cells via HIF-1α binding to a hypoxia-responsive element (HRE) located within the first intron (+813/+826) of the human apelin gene; siRNA knockdown of HIF-1α abolished hypoxia-induced apelin expression; apelin or APJ receptor knockdown inhibited hypoxia-induced endothelial cell proliferation in vitro and vessel regeneration in zebrafish. Transient transfection reporter assay, chromatin immunoprecipitation (ChIP), siRNA knockdown, in vivo zebrafish fin regeneration model Circulation research High 18617693
2007 Apelin-13 and apelin-36 produce cardioprotection against ischemia-reperfusion injury by activating the PI3K-Akt and p44/42 MAPK (RISK pathway) and delaying mitochondrial permeability transition pore (MPTP) opening; pharmacological inhibition of PI3K (LY294002) or MEK (UO126/MEK inhibitor 1) abolished the protective effects. In vivo open-chest rodent I/R model, in vitro Langendorff perfusion and isolated cardiomyocytes, Western blot for pathway activation, pharmacological inhibitors of PI3K and MEK Basic research in cardiology High 17694254
2007 Zebrafish apelin (ligand) and its receptor Agtrl1b (APJ homolog) control heart field formation during gastrulation by directing convergence of cardiac precursors from lateral plate mesoderm toward the midline; reduced or excess Apelin/Agtrl1b function caused deficiency of cardiac precursors and heart defects. Zebrafish loss-of-function and gain-of-function genetic experiments, in situ hybridization, confocal microscopy of cardiac precursor migration Developmental cell High 17336905
2015 Apelin-APJ signaling promotes brown adipocyte differentiation and browning of white adipocytes by increasing expression of brown adipogenic and thermogenic transcription factors via PI3K/Akt and AMPK signaling pathways; apelin also increases mitochondrial biogenesis, PGC1α and UCP1 expression, and oxygen consumption. In vitro adipocyte differentiation assays, PI3K/Akt and AMPK pathway pharmacological inhibitors, in vivo mouse model, gene expression and mitochondrial function assays The Journal of biological chemistry Medium 25931124
2015 APLN is robustly expressed in sprouting (tip) endothelial cells during angiogenesis and is re-activated in adult endothelial cells after ischemia; genetic ablation using Apln-CreER specifically labels sprouting but not quiescent vasculature, and abolishment of VEGF-VEGFR2 signaling reduced APLN expression in sprouting endothelium. Apln-CreER genetic lineage tracing mouse model, tumor angiogenesis and ischemia models, genetic ablation of sprouting endothelial cells Nature communications High 25597280
2015 Elabela (ELA)/Toddler activates the apelin receptor (APJ) in mammalian cells, causing receptor internalization, suppression of cAMP production (EC50 ~11 nM), ERK1/2 phosphorylation (EC50 ~14 nM), and weak intracellular calcium mobilization; ELA also induces angiogenesis in endothelial cells and relaxes mouse aortic blood vessels. Reconstituted HEK293 and CHO cell systems with GFP-APJ fusion, cAMP assay, ERK1/2 phosphorylation assay, calcium mobilization, aortic ring relaxation ex vivo Scientific reports High 25639753
2017 Crystal structure of human apelin receptor (APJR) at 2.6 Å resolution in complex with a 17-amino acid apelin mimetic peptide revealed a lactam-constrained, curved two-site ligand binding mode; mutation analysis and molecular dynamics simulations with apelin-13 identified key binding residues for apelin recognition and specificity. X-ray crystallography (2.6 Å), site-directed mutagenesis, molecular dynamics simulation Structure High 28528775
2016 Apelin-induced internalization of APJ occurs via clathrin-coated vesicles (CCVs) in a GRK2-mediated phosphorylation-dependent, β-arrestin1-independent, EPS15- and dynamin-dependent manner; [Pyr1]apelin-13 stimulation also causes rapid desensitization of APJ-mediated ERK1/2 (ppERK1/2) signaling through upstream APJ-specific adaptive changes rather than internalization. Dominant-negative mutant cDNA constructs (GRK2, β-arrestin1, EPS15, dynamin), semi-automated fluorescence imaging of HA-tagged APJ internalization in HEK293 cells, ERK1/2 phosphorylation assays Molecular and cellular endocrinology High 27492965
2014 Apelin-13 stimulation of APJ activates Gαi2 and Gαi3 through molecular rearrangement (rather than classical dissociation), while Gαo and Gαq are activated through classical dissociation; Gαi1 showed little change after apelin-13 stimulation. BRET and FRET in live HEK293 cells expressing APJ and fluorescent G-protein subunits Experimental cell research Medium 25193074
2006 Apelin and APJ are expressed in human osteoblasts; apelin stimulates osteoblast proliferation via APJ-dependent activation of PI3K/Akt (but not JNK, p38, or ERK1/2); siRNA-mediated APJ knockdown and LY294002 (PI3K inhibitor) abolished apelin-induced proliferation. RT-PCR, Western blot, siRNA knockdown of APJ, pharmacological PI3K inhibitor (LY294002), cell proliferation assay Regulatory peptides Medium 16563531
2018 Apelin inhibition reduces tumor angiogenesis, remodels the tumor microenvironment by reducing polymorphonuclear myeloid-derived suppressor cell infiltration, and prevents resistance to anti-angiogenic RTK inhibitor therapy; apelin loss alone accelerated tumor cell invasion, but combined apelin/VEGFR2 blockade was synergistically effective. Genetic knockout and pharmacological inhibition of apelin/APLNR in mammary and lung cancer mouse models, tumor microenvironment analysis EMBO molecular medicine Medium 31267692
2019 APLN is transcriptionally upregulated by active β-catenin, which binds to the APLN promoter to induce transcription in hepatocellular carcinoma; APLN activates PI3K/Akt via APLN receptor, leading to increased p-GSK3β and cyclin D1, promoting G1/S cell cycle progression and inhibiting apoptosis. β-catenin ChIP at APLN promoter, ectopic expression and siRNA knockdown, Western blot for PI3K/Akt pathway components, xenograft mouse model Theranostics Medium 31410213
2019 APLN protects against abdominal aortic aneurysm by preventing smooth muscle cell apoptosis and oxidative stress; APLN induces ACE2 expression in the vasculature; neutral endopeptidase (NEP) is a major enzyme that metabolizes and inactivates APLN-17 in human AAA tissue; a NEP-resistant APLN-17 analog (APLN-NMeLeu9-A2) ameliorated Ang II-mediated AAA in mice. Apln knockout mice, Ang II-induced AAA model, cultured murine and human aortic SMCs, pharmacological and genetic approaches, peptide analog design and synthesis, high-fat diet Ldlr-/- mouse model Proceedings of the National Academy of Sciences of the United States of America High 31189595
2022 Cryo-EM structures of fully active human apelin receptor (APJR) complexed with heterotrimeric G protein in both 2:1 (dimer:G protein) and 1:1 (monomer:G protein) stoichiometric ratios were determined; structural differences in G protein engagement between dimeric and monomeric APJR suggest a role for stoichiometry in GPCR-G protein coupling and downstream signaling; a small hydrophobic dimer interface was identified. Cryo-EM single-particle analysis with ELA and synthetic small molecule ligands Nature structural & molecular biology High 35817871
2018 A single residue mutation I109A (I109^3.32) in transmembrane domain 3 of APJ converts a balanced receptor into a G protein-biased receptor: it retains full ligand binding and G protein activation but is defective in GRK recruitment, β-arrestin recruitment, and downstream receptor-mediated ERK activation; molecular dynamics simulations indicated that the Phe-13 residue of apelin rotates to form new hydrophobic interactions with TM3 residues (F110, M113), stabilizing the biased conformation. Site-directed mutagenesis, G protein activation assay, GRK/β-arrestin recruitment assays, ERK phosphorylation, molecular dynamics simulation The Biochemical journal High 30409826
2024 Cryo-EM structures of APLNR-Gi1 complexes bound to three agonists with divergent signaling profiles identified 'twin hotspots' in APLNR as key determinants for G protein vs. β-arrestin signaling bias; structure-guided design produced G protein-biased agonists WN353 and WN561, which showed superior therapeutic effects against cardiac hypertrophy with reduced adverse effects compared to established APLNR agonists. Cryo-EM structure determination, functional signaling assays, structure-based rational drug design, in vivo cardiac hypertrophy pathophysiology experiments Cell High 38428423
2021 APLN is produced by Sertoli cells in response to high glucose, and hyper-activated APLN/APJ signaling in diabetic testes suppresses carnitine production and represses cell adhesion gene expression in Sertoli cells, causing blood-testis barrier (BTB) structural dysfunction and impaired spermatogenesis; pharmacological blockade of APLN/APJ with ML221 ameliorated BTB damage and improved spermatogenesis in diabetic db/db mice and cultured human testes. STRT-seq single-cell transcriptomics of human diabetic testes, in vitro Sertoli cell culture with high glucose, pharmacological inhibition with ML221, db/db diabetic mouse model, human testis culture Nature communications High 36443325
2021 Apelin induces cholangiocyte proliferation through Nox4/ROS/ERK-dependent signaling and activates hepatic stellate cells (HSCs) through intracellular ROS; APLN knockout or APJ antagonism (ML221) reduced bile duct ligation-induced cholangiocyte proliferation, liver inflammation, fibrosis, and angiogenesis in mice. Pharmacological inhibition (ML221, Nox4 inhibitor DPI, NAC, PD98059), APLN knockout mice, bile duct ligation model, Mdr2-/- mice, in vitro human biliary epithelial cells and HSC lines Hepatology High 32964473
2020 Elabela/Toddler and apelin bind differently to the apelin receptor: alanine scanning of ELA showed the C-terminus carries the key pharmacophore; Asp282/Asp284 of rat/human apelin receptor are critical for apelin binding and activity but are NOT involved in Elabela/Toddler activity, demonstrating distinct binding modes for the two endogenous ligands. Alanine scanning mutagenesis of ELA, site-directed mutagenesis of apelin receptor, binding affinity assays, cAMP inhibition assay, β-arrestin 2 recruitment assay in CHO cells FASEB journal High 32301550
2021 Apelin-13, pGlu1-apelin-13, apelin-17, apelin-36, Elabela-21, and Elabela-32 exhibit distinct signaling profiles at APJ: all activate both G protein-dependent (cAMP inhibition, Ca2+ mobilization, early-phase ERK activation) and β-arrestin-dependent (GRKs, β-arrestin 1/2, AP2) pathways in a dose-dependent manner, but with different bias ratios; Elabela-32 showed >1000-fold bias to β-arrestin-dependent signaling, and apelin-17 was biased toward β-arrestin-dependent signaling. cAMP assay, Ca2+ mobilization, ERK phosphorylation, β-arrestin 1/2 recruitment assay, GRK assay, AP2 assay in APJ-expressing cells Frontiers in pharmacology Medium 33746758
2017 Protamine binds the apelin receptor (APJ) with 390 nM affinity and acts as a full antagonist of both G protein and β-arrestin-dependent intracellular signaling; ex vivo and in vivo, protamine abolishes apelin-mediated angiogenesis, glucose tolerance improvement, and vasodilatation; protamine's APJ antagonist activity is fully reversed by heparin both in vitro and in vivo. Cell-based fluorescence microscopy screening assay for APJ antagonism, radioligand binding, cAMP and β-arrestin signaling assays, ex vivo angiogenesis and vasodilatation assays, in vivo glucose tolerance and angiogenesis tests, heparin reversal experiments FASEB journal High 28242772
2016 Apelin (APLN-13 and APLN-17) increases steroidogenesis (basal and IGF1-induced progesterone and estradiol) in human luteinized granulosa cells through activation of AKT and MAPK3/1 (ERK1/2) pathways and increased HSD3B protein expression; these effects are reversed by the APLNR antagonist ML221. RT-PCR, immunoblotting, pharmacological inhibitors of PI3K/Akt and MAPK, APJ antagonist ML221, steroid hormone ELISA Biology of reproduction Medium 27683264
2017 In bovine granulosa cells, APLN-13 and APLN-17 increase progesterone production via MAPK ERK1/2 and increase cell proliferation via AKT signaling (blocked by ML221); conversely, APLN-13 and APLN-17 arrest bovine oocytes at germinal vesicle stage during in vitro maturation, associated with decreased progesterone, inhibited ERK1/2 phosphorylation, and increased PRKA phosphorylation. In vitro bovine granulosa cell culture, in vitro oocyte maturation, pharmacological inhibition, immunoblotting for ERK1/2 and AKT, ML221 antagonist Reproduction Medium 28250234
2018 Apelin promotes lymphangiogenesis: APJ is expressed in lymphatic endothelial cells (LECs) and activates apelinergic signaling; apelin treatment enhances LEC migration, protects against UV-induced apoptosis, increases spheroid formation, stimulates in vitro tube formation, and promotes in vivo lymphatic microvessel invasion; apelin overexpression in tumor cells increases intratumoral lymphangiogenesis and lymph node metastasis. APJ expression in LECs by immunofluorescence, in vitro migration, apoptosis, 3D spheroid, tube formation assays, in vivo matrigel plug assay, apelin-overexpressing tumor xenograft model Oncotarget Medium 24962866
2018 Apelin deficiency in mice increases NADPH-stimulated superoxide levels in atria and slows atrial conduction velocities; apelin administration in mice with increased AF vulnerability reduced AF incidence/duration, prolonged atrial refractory periods, accelerated conduction velocity, and increased action potential duration; these electrophysiological effects were associated with increased atrial cardiomyocyte sodium currents. Apelin gene knockout mice, optical mapping of Langendorff-perfused isolated hearts, patch-clamp sodium current measurements, in vivo electrophysiology, NADPH oxidase activity assay JCI insight High 32879139
2018 The exerkine apelin is induced by muscle contraction; apelin or APLNR deficiency in mice causes age-dependent muscle dysfunction; restoration of apelin signaling enhances muscle function by triggering mitochondriogenesis, autophagy, and anti-inflammatory pathways in myofibers, and enhances regenerative capacity by targeting muscle stem cells. Apelin and APLNR knockout mice, apelin replacement strategies, exercise models, muscle stem cell assays, mitochondrial function assays, autophagy markers Nature medicine High 30061698
2015 Apelin controls fetal glucose homeostasis: intravenous apelin injection in pregnant rats increases transplacental glucose transport; intraperitoneal apelin in neonates increases glucose uptake in lung and muscle; the apelinergic system is expressed at the fetoplacental interface and in multiple fetal tissues; placenta releases high amounts of apelin in late gestation ex vivo. Intravenous apelin administration in pregnant rats, radiolabeled glucose transplacental transport assay, intraperitoneal injection in neonates with tissue glucose uptake measurement, RT-PCR and immunostaining for tissue expression Diabetes Medium 26631739
2017 APJ is expressed at cellular junctions in human umbilical vein endothelial cells (HUVECs) and may associate with PECAM-1; siRNA-mediated silencing of APJ influences shear-induced cytoskeletal remodeling, cellular elasticity, motility, attachment, and distribution of adhesion complexes in endothelial cells. siRNA knockdown of APJ, immunofluorescence localization, atomic force microscopy for cellular elasticity, motility and adhesion assays in HUVECs under shear flow Journal of cellular physiology Medium 29369349
2021 Apelin improves endothelial cell dysfunction in diabetes by decreasing apoptosis, reducing adhesion molecule expression, and increasing proliferation, angiogenesis, and expression of E-cadherin, VEGFR2, and Tie-2; these effects were dependent on APJ and downstream NF-κB pathways, as confirmed by endothelial cell-specific APJ knockout mice. Endothelial cell-specific APJ knockout mice, cultured endothelial cell assays, NF-κB pathway analysis, in vivo diabetic cardiomyopathy model The Journal of endocrinology Medium 33504680
2017 Apelin is identified as a factor secreted by brain endothelial cells (by mass spectrometry proteomics) that maintains glioblastoma stem-like cell expansion; genetic and pharmacological targeting of the apelin receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma stem-like cells in vitro and suppresses tumor growth in vivo. Mass spectrometry proteomic characterization of brain endothelial cell secretome, genetic apelin receptor targeting, competitive APJ antagonists, in vivo xenograft GBM model Brain Medium 29053791

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Emerging roles of apelin in biology and medicine. Pharmacology & therapeutics 326 15907343
2018 The exerkine apelin reverses age-associated sarcopenia. Nature medicine 316 30061698
2013 The apelin receptor APJ: journey from an orphan to a multifaceted regulator of homeostasis. The Journal of endocrinology 269 23943882
2011 Apelin, diabetes, and obesity. Endocrine 222 21725702
2008 Hypoxia-induced apelin expression regulates endothelial cell proliferation and regenerative angiogenesis. Circulation research 215 18617693
2018 The Role of Apelin in Cardiovascular Diseases, Obesity and Cancer. Frontiers in physiology 191 29875677
2007 Apelin-13 and apelin-36 exhibit direct cardioprotective activity against ischemia-reperfusion injury. Basic research in cardiology 184 17694254
2015 Elabela-apelin receptor signaling pathway is functional in mammalian systems. Scientific reports 170 25639753
2008 The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochemical pharmacology 150 18272138
2007 Apelin and its receptor control heart field formation during zebrafish gastrulation. Developmental cell 142 17336905
2005 Apelin signalling: a promising pathway from cloning to pharmacology. Cellular signalling 142 15601620
2018 Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacology & therapeutics 132 29807055
2008 The role of apelin in cardiovascular function and heart failure. European journal of heart failure 127 18583184
2015 Apelin, Elabela/Toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends in pharmacological sciences 115 26143239
2017 Structural Basis for Apelin Control of the Human Apelin Receptor. Structure (London, England : 1993) 108 28528775
2018 Review: Apelin in disease. Clinica chimica acta; international journal of clinical chemistry 107 29750964
2015 Genetic targeting of sprouting angiogenesis using Apln-CreER. Nature communications 105 25597280
2013 Apelin and its receptor APJ in cardiovascular diseases. Clinica chimica acta; international journal of clinical chemistry 105 24055369
2010 Translational promise of the apelin--APJ system. Heart (British Cardiac Society) 102 20584856
2006 Apelin and visfatin: unique "beneficial" adipokines upregulated in obesity? Medical science monitor : international medical journal of experimental and clinical research 98 16733497
2015 Apelin Enhances Brown Adipogenesis and Browning of White Adipocytes. The Journal of biological chemistry 93 25931124
2020 Apelin/APJ system: an emerging therapeutic target for respiratory diseases. Cellular and molecular life sciences : CMLS 91 32128601
2019 Apelin inhibition prevents resistance and metastasis associated with anti-angiogenic therapy. EMBO molecular medicine 91 31267692
2017 Temporal Expression of Apelin/Apelin Receptor in Ischemic Stroke and its Therapeutic Potential. Frontiers in molecular neuroscience 85 28167898
2012 Neuroprotection of apelin and its signaling pathway. Peptides 85 22820556
2021 The Role of Apelin/Apelin Receptor in Energy Metabolism and Water Homeostasis: A Comprehensive Narrative Review. Frontiers in physiology 82 33679444
2021 The therapeutic potential of apelin in kidney disease. Nature reviews. Nephrology 81 34389827
2015 Effects of apelin on the cardiovascular system. Heart failure reviews 81 25652330
2017 Pharmacological targeting of apelin impairs glioblastoma growth. Brain : a journal of neurology 79 29053791
2015 Apelin receptors: From signaling to antidiabetic strategy. European journal of pharmacology 78 26007641
2022 The Role of Apelin-APJ System in Diabetes and Obesity. Frontiers in endocrinology 77 35355561
2014 Apelin promotes lymphangiogenesis and lymph node metastasis. Oncotarget 77 24962866
2018 Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides 75 29684595
2015 The ACE2/Apelin Signaling, MicroRNAs, and Hypertension. International journal of hypertension 75 25815211
2007 Modulation of apelin and APJ receptor in normal and preeclampsia-complicated placentas. Histology and histopathology 74 17128405
2023 Targeting the apelin system for the treatment of cardiovascular diseases. Cardiovascular research 73 37956047
2016 Apelin/APJ system and cancer. Clinica chimica acta; international journal of clinical chemistry 73 27083318
2011 Apelin and pulmonary hypertension. Pulmonary circulation 72 22140623
2018 Apelin in Reproductive Physiology and Pathology of Different Species: A Critical Review. International journal of endocrinology 71 29977292
2006 Apelin and its receptor are expressed in human osteoblasts. Regulatory peptides 69 16563531
2016 Apelin (APLN) and Apelin Receptor (APLNR) in Human Ovary: Expression, Signaling, and Regulation of Steroidogenesis in Primary Human Luteinized Granulosa Cells. Biology of reproduction 67 27683264
2022 Apelin/APJ system in inflammation. International immunopharmacology 62 35605524
2019 Targeting APLN/APLNR Improves Antiangiogenic Efficiency and Blunts Proinvasive Side Effects of VEGFA/VEGFR2 Blockade in Glioblastoma. Cancer research 62 30718358
2019 APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target. Theranostics 60 31410213
2020 Role of Apelin/APJ axis in cancer development and progression. Advances in medical sciences 59 32087570
2022 Targeting APLN/APJ restores blood-testis barrier and improves spermatogenesis in murine and human diabetic models. Nature communications 58 36443325
2022 Structural insight into apelin receptor-G protein stoichiometry. Nature structural & molecular biology 55 35817871
2019 Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs. Proceedings of the National Academy of Sciences of the United States of America 55 31189595
2013 Apelin and APJ, a novel critical factor and therapeutic target for atherosclerosis. Acta biochimica et biophysica Sinica 55 23588025
2016 Inhibition of the apelin/apelin receptor axis decreases cholangiocarcinoma growth. Cancer letters 52 27894959
2014 Apelin/APJ system: a promising therapy target for hypertension. Molecular biology reports 48 24990699
2014 The protective effect of apelin on ischemia/reperfusion injury. Peptides 47 25447414
2015 Apelin/APJ signaling in hypoxia-related diseases. Clinica chimica acta; international journal of clinical chemistry 46 26436483
2020 The Apelin/APJ System in Psychosis and Neuropathy. Frontiers in pharmacology 44 32231577
2017 Apelin (APLN) regulates progesterone secretion and oocyte maturation in bovine ovarian cells. Reproduction (Cambridge, England) 43 28250234
2016 Apelin/APJ system: A bifunctional target for cardiac hypertrophy. International journal of cardiology 43 27979574
2016 Apelin-13 in blood pressure regulation and cardiovascular disease. Current opinion in nephrology and hypertension 40 27258138
2020 Apelin Controls Angiogenesis-Dependent Glioblastoma Growth. International journal of molecular sciences 39 32545380
2019 Elabela and Apelin actions in healthy and pathological pregnancies. Cytokine & growth factor reviews 39 30910349
2021 The Apelin-Apelin Receptor Axis Triggers Cholangiocyte Proliferation and Liver Fibrosis During Mouse Models of Cholestasis. Hepatology (Baltimore, Md.) 37 32964473
2021 Apelin pathway in cardiovascular, kidney, and metabolic diseases: Therapeutic role of apelin analogs and apelin receptor agonists. Peptides 37 34801627
2018 Function and regulation of apelin/APJ system in digestive physiology and pathology. Journal of cellular physiology 35 30390294
2017 Novel pathogenesis: regulation of apoptosis by Apelin/APJ system. Acta biochimica et biophysica Sinica 35 28407045
2015 The Apelin-APJ System in the Evolution of Heart Failure. Clujul medical (1957) 35 26528040
2024 Structure-based design of non-hypertrophic apelin receptor modulator. Cell 33 38428423
2021 Apelin, APJ, and ELABELA: Role in Placental Function, Pregnancy, and Foetal Development-An Overview. Cells 32 35011661
2015 Apelin Controls Fetal and Neonatal Glucose Homeostasis and Is Altered by Maternal Undernutrition. Diabetes 32 26631739
2016 Agonist-induced internalization and desensitization of the apelin receptor. Molecular and cellular endocrinology 30 27492965
2021 Neuroprotective gain of Apelin/APJ system. Neuropeptides 29 33640616
2010 Effect of apelin-apelin receptor system in postischaemic myocardial protection: a pharmacological postconditioning tool? Antioxidants & redox signaling 29 20615122
2021 Apelin/APJ relieve diabetic cardiomyopathy by reducing microvascular dysfunction. The Journal of endocrinology 28 33504680
2023 Neuroprotective Roles of Apelin-13 in Neurological Diseases. Neurochemical research 27 36745269
2021 The Effects of Apelin and Elabela Ligands on Apelin Receptor Distinct Signaling Profiles. Frontiers in pharmacology 27 33746758
2020 Apelin/Apelin receptor: A new therapeutic target in Polycystic Ovary Syndrome. Life sciences 27 32835696
2022 Apelin/APJ system: an emerging therapeutic target for neurological diseases. Molecular biology reports 26 36378421
2021 Apelin/Apelin Receptor System: Molecular Characteristics, Physiological Roles, and Prospects as a Target for Disease Prevention and Pharmacotherapy. Current molecular pharmacology 26 32484774
2021 Apelin and Vasopressin: The Yin and Yang of Water Balance. Frontiers in endocrinology 26 34880830
2017 Protamine is an antagonist of apelin receptor, and its activity is reversed by heparin. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26 28242772
2017 Role of the Vasopressin/Apelin Balance and Potential Use of Metabolically Stable Apelin Analogs in Water Metabolism Disorders. Frontiers in endocrinology 26 28620355
2009 Apelin and its receptor APJ in human aortic valve stenosis. The Journal of heart valve disease 26 20099713
2014 Dynamics of apelin receptor/G protein coupling in living cells. Experimental cell research 25 25193074
2021 The therapeutic potentials of apelin in obesity-associated diseases. Molecular and cellular endocrinology 24 33838166
2020 Apelin-potential therapy for COVID-19? Journal of molecular and cellular cardiology 24 32562701
2019 Apelin and apelin receptor expression in renal cell carcinoma. British journal of cancer 24 30783205
2020 A patent review of apelin receptor (APJR) modulators (2014-2019). Expert opinion on therapeutic patents 23 32066307
2020 Elabela/Toddler and apelin bind differently to the apelin receptor. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 32301550
2020 Apelin-13 prevents hippocampal synaptic plasticity impairment in Parkinsonism rats. Journal of chemical neuroanatomy 23 33161074
2014 Apelin and G212A apelin receptor gene polymorphism in obese and diabese youth. Pediatric obesity 23 25060841
2022 The Apelin/APLNR system modulates tumor immune response by reshaping the tumor microenvironment. Gene 22 35598689
2018 The apelin receptor influences biomechanical and morphological properties of endothelial cells. Journal of cellular physiology 22 29369349
2011 Apelin gene polymorphism influences apelin expression and obesity phenotypes in Chinese women. The American journal of clinical nutrition 22 21775567
2023 Therapeutic potential of apelin and Elabela in cardiovascular disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 20 37562237
2021 A network map of apelin-mediated signaling. Journal of cell communication and signaling 20 33797707
2019 Evaluation of serum apelin-13 and apelin-36 concentrations in preeclamptic pregnancies. The journal of obstetrics and gynaecology research 20 31595589
2022 Targeting the elabela/apelin-apelin receptor axis as a novel therapeutic approach for hypertension. Chinese medical journal 19 34608073
2020 Apelin increases atrial conduction velocity, refractoriness, and prevents inducibility of atrial fibrillation. JCI insight 19 32879139
2022 Potential Therapeutic Role for Apelin and Related Peptides in Diabetes: An Update. Clinical medicine insights. Endocrinology and diabetes 18 35177945
2018 GPCR structure and function relationship: identification of a biased apelin receptor mutant. The Biochemical journal 18 30409826
2017 The effect of apelin on the functions of peritoneal macrophages. Physiological research 18 28248533
2022 Apelin and Apelin Receptor in Follicular Granulosa Cells of Buffalo Ovaries: Expression and Regulation of Steroidogenesis. Frontiers in endocrinology 17 35355567

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