{"gene":"APELA","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2015,"finding":"APELA (Elabela/Toddler) binds directly to the APJ receptor with high affinity (Kd = 0.51 nM), competes with apelin for the same binding site, and activates the inhibitory G protein (Gi) pathway by inhibiting forskolin-stimulated cAMP production and inducing ERK1/2 phosphorylation.","method":"Chimeric ligand binding assay, radioligand competition, cAMP inhibition assay, ERK1/2 phosphorylation (Western blot), in vivo diuresis/water intake studies in adult rats","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding measured by competition assay with Kd determination, Gi signaling confirmed by cAMP inhibition, ERK phosphorylation, and in vivo functional readout; multiple orthogonal methods in one study","pmids":["25995451"],"is_preprint":false},{"year":2015,"finding":"APELA binds to apelin receptors in the adult rodent heart (non-cardiomyocyte fraction), increases cardiac contractility and induces coronary vasodilation, and this inotropic effect is accompanied by ERK1/2 phosphorylation; pharmacological inhibition of ERK1/2 markedly attenuates apela-induced inotropy.","method":"Receptor binding in heart tissue, isolated adult rat heart perfusion, Western blot for ERK1/2 phosphorylation, pharmacological ERK1/2 inhibitor experiments","journal":"Basic research in cardiology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal binding evidence, functional ex vivo cardiac assay, causal pathway confirmed by pharmacological inhibition, multiple methods in single lab","pmids":["26611206"],"is_preprint":false},{"year":2017,"finding":"Loss of Apela in mice (CRISPR/Cas9 null allele) causes low-penetrance cardiovascular defects, vascular remodeling defects, and aberrant upregulation of erythroid and myeloid markers. Double-mutant analysis showed that Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, and combined loss causes lethal cardiac defects.","method":"CRISPR/Cas9 knockout, 3D micro-CT, transcriptomics (RNA-seq), double-mutant epistasis analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic null allele, multiple phenotypic readouts, epistasis with Apelin double mutant establishes pathway independence; replicated across multiple embryos","pmids":["28854362"],"is_preprint":false},{"year":2015,"finding":"The Apela RNA functions as a regulatory (non-coding) RNA in mouse embryonic stem cells that interacts with hnRNPL protein, thereby preventing mitochondrial localization and activation of p53. This forms a tri-element negative feedback loop (p53 → represses Apela → Apela/hnRNPL suppresses p53 mitochondrial activation) regulating p53-mediated DNA damage-induced apoptosis. The coding ability of Apela is dispensable for this function.","method":"RNA–protein interaction (Apela RNA pulldown with hnRNPL), genetic depletion (shRNA knockdown), co-immunoprecipitation, subcellular fractionation of p53, apoptosis assay in ESCs after DNA damage","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNA–protein interaction validated by pulldown, functional rescue experiments, subcellular localization change demonstrated by fractionation, coding-null mutant confirms non-coding mechanism; multiple orthogonal methods","pmids":["25936916"],"is_preprint":false},{"year":2017,"finding":"APELA promotes tumor cell growth and migration in ovarian clear cell carcinoma (OCCC) through an APLNR-independent pathway in cells lacking APLNR expression, and affects cell-cycle progression in a p53-dependent manner; APELA knockdown induced p53 expression.","method":"CRISPR/Cas9 APELA knockout in OCCC cell lines, recombinant APELA peptide addition, cell growth/migration assays, cell-cycle analysis, p53 expression by Western blot","journal":"Gynecologic oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR knockout with multiple cellular phenotypic readouts, APLNR-independence demonstrated by receptor expression status; single lab, limited mechanistic depth","pmids":["29079036"],"is_preprint":false},{"year":2020,"finding":"The APELA precursor (proELA) is cleaved by furin to generate mature ELA; site-directed mutagenesis of the furin cleavage site improves ELA antitumorigenic activity. Mature ELA suppresses kidney tumor cell growth, migration, and survival through mTORC1 signaling activation.","method":"Site-directed mutagenesis of furin cleavage site, pharmacological furin inhibition, mTORC1 signaling assays, tumor cell growth/migration assays in vitro, xenograft mouse model with sunitinib combination","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — site-directed mutagenesis of catalytic processing site, in vitro mechanistic assays, and in vivo xenograft validation; multiple orthogonal methods in one study","pmids":["32516140"],"is_preprint":false},{"year":2017,"finding":"Apela isoforms (apela-54, -32, and -11) exhibit distinct membrane-binding behaviors: apela-32 interacts with DPC, SDS, and LPPG micelles (inducing α-helical character), while apela-11 interacts preferentially with SDS and LPPG micelles (inducing β-turn character), indicating isoform- and headgroup-dependent membrane interactions that may influence apelin receptor recognition.","method":"NMR spectroscopy (pulsed-field gradient diffusion NMR, chemical shift perturbation), circular dichroism (CD) spectropolarimetry","journal":"Biochimica et biophysica acta. Biomembranes","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — rigorous biophysical NMR and CD methods but functional consequence for receptor binding inferred rather than directly demonstrated; single lab","pmids":["28132903"],"is_preprint":false},{"year":2021,"finding":"Apela inhibits angiotensin II-induced inflammatory responses in renal glomerular endothelial cells (including MCP-1, TNF-α, ICAM-1, VCAM-1 expression and THP-1 cell adhesion) by inhibiting the NFκB signaling pathway; blockade of the APJ receptor abolishes these inhibitory effects, confirming APJ-dependence.","method":"In vitro cell treatment (RGECs), Western blot for phospho-NFκB, cytokine measurement, APJ inhibitor (pharmacological blockade), THP-1 adhesion assay; in vivo CRS mouse model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — APJ dependence confirmed by pharmacological antagonism, NFκB pathway implicated by phosphorylation Western blot, multiple readouts in single lab","pmids":["34516679"],"is_preprint":false},{"year":2022,"finding":"ELA-11 (the furin-cleaved 11-residue fragment of APELA) protects cardiomyocytes against oxidative stress-induced apoptosis through PI3K/AKT and ERK/MAPK signaling pathways, and its protective effect is mediated through the APJ receptor (blocked by ML221, an APJ antagonist).","method":"In vivo DOX-injured mouse model, in vitro cardiomyocyte assays with DOX and CoCl2, Western blot for PI3K/AKT and ERK/MAPK, pharmacological APJ antagonist (ML221) blocking experiment","journal":"Frontiers in pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — APJ receptor dependency confirmed by pharmacological antagonism, signaling pathway confirmed by Western blot, in vivo and in vitro concordant results; single lab","pmids":["36160397"],"is_preprint":false},{"year":2020,"finding":"ELABELA improves endothelial cell function (viability, migration, tube formation) via the ELA–APJ axis by activating PI3K/Akt signaling; the PI3K inhibitor wortmannin blocks ELA-induced effects and also blocks ELA-induced APJ receptor upregulation.","method":"HUVEC and EA.hy926 cell treatment, CCK-8 viability, scratch-wound, tube formation assays, Western blot for PI3K/Akt, pharmacological PI3K inhibition (wortmannin)","journal":"Clinical and experimental pharmacology & physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PI3K/Akt pathway confirmed by pharmacological inhibition with functional readouts; single lab, two cell lines","pmids":["32687618"],"is_preprint":false},{"year":2018,"finding":"In non-mammalian vertebrates (zebrafish, spotted gar, pigeon), APELA peptides activate GPR25 (an orphan GPCR) to inhibit cAMP production and induce receptor internalization; human GPR25 was NOT activated by Apela under the same conditions.","method":"pGL3-CRE-luciferase reporter assay for cAMP inhibition, confocal microscopy for receptor internalization, heterologous expression in HEK293 cells","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay with multiple non-mammalian orthologs, negative result for human GPR25 explicitly documented; single lab","pmids":["29727602"],"is_preprint":false},{"year":2021,"finding":"ELA-32 (Apela) in human plasma has a half-life of ~47 min and in kidney homogenates ~44 s. The primary metabolic fragments generated include ELA-11, ELA-16, ELA-19, and ELA-20; ELA-16 was identified as a potentially more stable fragment.","method":"LC-MS/MS (Orbitrap) metabolic stability assay in human plasma and kidney homogenates, PEAKS Studio peptide fragment analysis","journal":"Peptides","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — rigorous LC-MS/MS identification of metabolites with defined half-life values; single lab but well-controlled in vitro biochemistry","pmids":["34455010"],"is_preprint":false},{"year":2022,"finding":"Apela gene therapy (AAV-ELA32) in monocrotaline-induced pulmonary arterial hypertension rats upregulates KLF2/eNOS and BMPRII/SMAD4 signaling in pulmonary arterioles, inhibits endothelial-to-mesenchymal transition, and reduces pulmonary arteriolar muscularization.","method":"AAV-mediated gene delivery, right ventricular systolic pressure measurement, histopathology, immunofluorescence, Western blotting for KLF2/eNOS and BMPRII/SMAD4","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene therapy model with defined molecular pathway readouts; single lab, multiple signaling endpoints measured","pmids":["35747913"],"is_preprint":false},{"year":2019,"finding":"Two rare variants in the 5'-UTR of the APELA gene (c.-306A>G and c.-145A>G) impair transcriptional activity of APELA by altering promoter function, as demonstrated by luciferase reporter assays in HEK293 and HTR-8/SVneo cells.","method":"Sanger sequencing, luciferase reporter assay in HEK293 and HTR-8/SVneo cells","journal":"Prenatal diagnosis","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single functional assay (luciferase) in cell lines; no protein-level or in vivo validation; single lab","pmids":["30719741"],"is_preprint":false},{"year":2024,"finding":"In zebrafish fin regeneration, Apela selectively accumulates in newly formed fin tissue and vessels; morpholino-mediated knockdown of Apela prevents vessel remodeling, while exogenous Apela peptide mediates plexus repression and promotes arterial development in regenerated fins. Apela also regulates expression of vascular remodeling genes including VWF, IGFBP3, ESM1, VEGFR2, Apln, and Aplnr.","method":"In vivo fin regeneration model in zebrafish, morpholino knockdown, exogenous peptide rescue, gene expression analysis","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino loss-of-function with rescue by exogenous peptide in zebrafish in vivo model; single lab but orthogonal loss-of-function and gain-of-function","pmids":["38355946"],"is_preprint":false},{"year":2025,"finding":"ELA-11 suppresses macrophage foam cell formation, M1 polarization, and apoptosis via inhibition of the AKT–endoplasmic reticulum (ER) stress pathway; mPEG@ELA-11 (a pH-responsive conjugate) reduces atherosclerotic plaque area more effectively than free ELA-11 in ApoE-/- mice.","method":"In vitro RAW264.7 macrophage assays (foam cell formation, polarization, apoptosis), Western blot for AKT-ER stress pathway, in vivo ApoE-/- mouse atherosclerosis model, pH-responsive release characterization","journal":"BME frontiers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro pathway mechanistic data supported by in vivo mouse model; single lab, multiple functional readouts","pmids":["41306397"],"is_preprint":false}],"current_model":"APELA (Elabela/Toddler/ELA) is a secreted peptide hormone that functions as a high-affinity endogenous ligand for the APJ (APLNR) G protein-coupled receptor, activating Gi signaling to inhibit cAMP production and stimulate ERK1/2 and PI3K/AKT phosphorylation; its precursor proELA is processed by furin into mature isoforms (ELA-32, ELA-11, etc.) with distinct biological activities including regulation of cardiac contractility, vascular tone, fluid homeostasis, and angiogenesis, while the APELA RNA itself also functions independently as a non-coding regulatory RNA in embryonic stem cells, where it sequesters hnRNPL to prevent mitochondrial p53 activation and thereby modulates the apoptotic response to DNA damage."},"narrative":{"mechanistic_narrative":"APELA (Elabela/Toddler/ELA) is a secreted peptide hormone that serves as a high-affinity endogenous ligand for the APJ (APLNR) receptor, where it competes with apelin for the same site, activates inhibitory Gi signaling to suppress forskolin-stimulated cAMP, and drives ERK1/2 phosphorylation [PMID:25995451]. Through this APJ axis it regulates cardiovascular physiology — increasing cardiac contractility and inducing coronary vasodilation in an ERK1/2-dependent manner [PMID:26611206] — and genetic ablation in mice produces cardiovascular and vascular remodeling defects together with aberrant erythroid/myeloid marker expression, with epistasis showing APELA acts on early Aplnr-expressing mesoderm independently of apelin [PMID:28854362]. The APELA precursor (proELA) is processed by furin into mature isoforms, and disrupting the furin cleavage site alters its biological activity [PMID:32516140, PMID:34455010], with distinct fragments such as ELA-11 signaling through APJ to activate PI3K/AKT and ERK/MAPK and to protect against oxidative and inflammatory stress [PMID:36160397, PMID:32687618]. Beyond its receptor-mediated peptide role, the APELA RNA acts independently as a non-coding regulatory transcript in embryonic stem cells, binding hnRNPL to block mitochondrial p53 localization and thereby restrain DNA-damage-induced apoptosis in a manner that does not require its coding capacity [PMID:25936916]. APELA also exerts APLNR-independent, p53-linked effects on tumor cell proliferation [PMID:29079036].","teleology":[{"year":2015,"claim":"Established APELA as a bona fide endogenous APJ ligand, answering whether it engages the same receptor as apelin and through which G protein pathway.","evidence":"Radioligand competition with Kd determination, cAMP inhibition and ERK1/2 Western blot, plus in vivo diuresis studies in rats","pmids":["25995451"],"confidence":"High","gaps":["Structural basis of the APELA-APJ interaction not resolved","Relative contribution of individual isoforms to receptor activation not dissected"]},{"year":2015,"claim":"Revealed a coding-independent function: the APELA RNA itself is a regulatory non-coding RNA controlling the p53 apoptotic response, separating the transcript's role from the peptide's.","evidence":"RNA pulldown with hnRNPL, shRNA depletion, p53 subcellular fractionation, and apoptosis assays in mouse ESCs, with a coding-null mutant","pmids":["25936916"],"confidence":"High","gaps":["Structural detail of the APELA RNA-hnRNPL interaction unknown","Whether this RNA function operates outside ESCs unaddressed"]},{"year":2015,"claim":"Demonstrated APELA's physiological cardiac role and confirmed ERK1/2 as the effector mediating its inotropic action.","evidence":"Receptor binding in heart tissue and isolated rat heart perfusion with pharmacological ERK1/2 inhibition","pmids":["26611206"],"confidence":"High","gaps":["Cell type within heart mediating contractility not defined beyond non-cardiomyocyte fraction","Chronic versus acute effects not distinguished"]},{"year":2017,"claim":"Genetic loss-of-function placed APELA in early mesodermal/cardiovascular development and showed it acts independently of apelin on shared APJ-expressing populations.","evidence":"CRISPR/Cas9 null mice, micro-CT, RNA-seq, and Apelin double-mutant epistasis","pmids":["28854362"],"confidence":"High","gaps":["Basis of low penetrance unexplained","Molecular driver of erythroid/myeloid dysregulation not identified"]},{"year":2017,"claim":"Identified an APLNR-independent, p53-linked APELA activity in cancer cells, broadening its mechanism beyond receptor signaling.","evidence":"CRISPR knockout and recombinant peptide addition in OCCC lines lacking APLNR, with cell-cycle and p53 Western blot readouts","pmids":["29079036"],"confidence":"Medium","gaps":["The receptor or effector mediating the APLNR-independent effect unknown","Direct link between APELA and p53 induction not mechanistically defined"]},{"year":2017,"claim":"Characterized isoform-specific membrane interactions that may shape receptor recognition, providing a biophysical basis for functional differences among isoforms.","evidence":"NMR diffusion/chemical shift and CD spectropolarimetry with micelle systems","pmids":["28132903"],"confidence":"Medium","gaps":["Functional consequence for receptor binding inferred, not directly shown","Relevance to native membranes untested"]},{"year":2018,"claim":"Mapped an alternative receptor (GPR25) for APELA in non-mammalian vertebrates while showing human GPR25 is not activated, clarifying receptor usage across species.","evidence":"CRE-luciferase cAMP reporter and receptor internalization in HEK293 cells across orthologs","pmids":["29727602"],"confidence":"Medium","gaps":["Physiological role of GPR25 signaling in vivo unestablished","Why human GPR25 is unresponsive not explained"]},{"year":2020,"claim":"Defined furin as the maturation protease for proELA and linked processing to mTORC1-dependent anti-tumor activity, connecting precursor handling to function.","evidence":"Site-directed mutagenesis of the furin site, furin inhibition, mTORC1 assays, and kidney tumor xenografts","pmids":["32516140"],"confidence":"High","gaps":["How mature ELA engages mTORC1 mechanistically not resolved","Receptor dependence of the anti-tumor effect not pinned down"]},{"year":2020,"claim":"Showed the ELA-APJ axis promotes endothelial function via PI3K/Akt, extending APELA's vascular signaling repertoire.","evidence":"HUVEC/EA.hy926 viability, migration, tube formation with wortmannin inhibition and Western blot","pmids":["32687618"],"confidence":"Medium","gaps":["In vivo angiogenic relevance not tested in this study","Single-pathway focus leaves crosstalk unaddressed"]},{"year":2021,"claim":"Determined APELA peptide metabolic stability and the fragment cascade, identifying the bioactive/stable species generated in plasma and kidney.","evidence":"LC-MS/MS metabolic stability assays in human plasma and kidney homogenates","pmids":["34455010"],"confidence":"Medium","gaps":["Receptor activity of each metabolite not measured here","In vivo clearance in humans not validated"]},{"year":2021,"claim":"Demonstrated APJ-dependent anti-inflammatory signaling via NFκB inhibition in renal endothelium, linking APELA to renoprotection.","evidence":"RGEC treatment with APJ pharmacological blockade, phospho-NFκB Western blot, cytokine and adhesion assays, plus a CRS mouse model","pmids":["34516679"],"confidence":"Medium","gaps":["Direct receptor-to-NFκB coupling mechanism not defined","Single-lab in vivo confirmation"]},{"year":2022,"claim":"Showed ELA-11 protects cardiomyocytes from oxidative apoptosis through APJ-dependent PI3K/AKT and ERK/MAPK signaling, defining a specific cardioprotective fragment.","evidence":"DOX-injured mouse and cardiomyocyte assays with ML221 APJ antagonist and pathway Western blots","pmids":["36160397"],"confidence":"Medium","gaps":["Why the 11-residue fragment is preferentially active not explained","Long-term cardioprotection not assessed"]},{"year":2022,"claim":"Established a therapeutic vascular role in pulmonary hypertension via KLF2/eNOS and BMPRII/SMAD4 signaling and EndMT suppression.","evidence":"AAV-ELA32 gene therapy in monocrotaline PAH rats with hemodynamic, histologic, and Western blot readouts","pmids":["35747913"],"confidence":"Medium","gaps":["Whether effects are APJ-mediated not directly tested","Causal ordering of the two signaling axes unresolved"]},{"year":2024,"claim":"Defined APELA as a regulator of vessel remodeling and arterial specification during regeneration through control of vascular gene programs.","evidence":"Zebrafish fin regeneration with morpholino knockdown and exogenous peptide rescue plus gene expression analysis","pmids":["38355946"],"confidence":"Medium","gaps":["Direct targets among the regulated genes not distinguished from indirect","Receptor mediating regenerative effect not specified"]},{"year":2025,"claim":"Extended ELA-11's anti-inflammatory action to atherosclerosis via AKT-ER stress inhibition in macrophages, with a delivery strategy improving efficacy.","evidence":"RAW264.7 macrophage assays, AKT-ER stress Western blots, and an mPEG@ELA-11 conjugate in ApoE-/- mice","pmids":["41306397"],"confidence":"Medium","gaps":["Receptor mediating the macrophage effect not established","Mechanistic link between AKT and ER stress not fully resolved"]},{"year":null,"claim":"How APELA's two distinct modes — secreted APJ-ligand peptide signaling and coding-independent RNA regulation of p53 — are coordinated within a single cell, and the identity of the receptor(s) mediating its multiple APLNR-independent activities, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking RNA and peptide functions","APLNR-independent receptor(s) unidentified","No structural model of APELA-receptor or APELA-hnRNPL complexes"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,1,8]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,10]},{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,5,11]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,8,9]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[2,14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[3,8]}],"complexes":[],"partners":["APLNR","HNRNPL","FURIN","GPR25"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0DMC3","full_name":"Apelin receptor early endogenous ligand","aliases":["Protein Elabela","ELA","Protein Toddler"],"length_aa":54,"mass_kda":6.6,"function":"Peptide hormone that functions as endogenous ligand for the G-protein-coupled apelin receptor (APLNR/APJ), that plays a role in the regulation of normal cardiovascular function and fluid homeostasis (PubMed:25639753, PubMed:28137936, PubMed:35817871). Functions as a balanced agonist activating both G(i) protein pathway and beta-arrestin pathway of APLNR (PubMed:35817871). Downstream G proteins activation, apelin can inhibit cAMP production and activate key intracellular effectors such as ERKs (PubMed:35817871). On the other hand, APLNR activation induces beta-arrestin recruitment to the membrane leading to desensitization and internalization of the receptor (PubMed:35817871). Required for mesendodermal differentiation, blood vessels formation and heart morphogenesis during early development and for adult cardiovascular homeostasis (PubMed:25639753, PubMed:28137936). Acts as a motogen by promoting mesendodermal cell migration during gastrulation by binding and activating APLNR. Acts as an early embryonic regulator of cellular movement with a role in migration and development of cardiac progenitor cells. May act as a chemoattractant for the activation of angioblast migration toward the embryonic midline, i.e. the position of the future vessel formation, during vasculogenesis. Positively regulates sinus venosus (SV)-derived endothelial cells migration into the developing heart to promote coronary blood vessel sprouting. Plays a role in placental vascular development; promotes placental trophoblast invasion and spiral artery remodeling in the uterus. Involved in the regulation of maternal cardiovascular homeostasis to prevent gestational hypertension and for potent cardioprotective functions during heart failure. Mediates myocardial contractility in an ERK1/2-dependent manner (By similarity)","subcellular_location":"Secreted; Secreted, extracellular space","url":"https://www.uniprot.org/uniprotkb/P0DMC3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/APELA","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/APELA","total_profiled":1310},"omim":[{"mim_id":"615594","title":"APELIN RECEPTOR EARLY ENDOGENOUS LIGAND; APELA","url":"https://www.omim.org/entry/615594"},{"mim_id":"600052","title":"APELIN RECEPTOR; APLNR","url":"https://www.omim.org/entry/600052"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"breast","ntpm":1.4},{"tissue":"kidney","ntpm":2.0},{"tissue":"prostate","ntpm":4.0}],"url":"https://www.proteinatlas.org/search/APELA"},"hgnc":{"alias_symbol":["Ende","ELA","tdl"],"prev_symbol":[]},"alphafold":{"accession":"P0DMC3","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DMC3","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0DMC3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0DMC3-F1-predicted_aligned_error_v6.png","plddt_mean":72.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=APELA","jax_strain_url":"https://www.jax.org/strain/search?query=APELA"},"sequence":{"accession":"P0DMC3","fasta_url":"https://rest.uniprot.org/uniprotkb/P0DMC3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0DMC3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0DMC3"}},"corpus_meta":[{"pmid":"2460224","id":"PMC_2460224","title":"Altered expression of NM23, a gene 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/42231755","citation_count":0,"is_preprint":false},{"pmid":"42011928","id":"PMC_42011928","title":"Substrate-Binding Site Engineering of Thermomyces dupontii Lipase (TDL) to Improve Selectivity for the Synthesis of Functional sn-1,3-Diacylglycerol.","date":"2026","source":"Journal of agricultural and food chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42011928","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":45525,"output_tokens":4260,"usd":0.100237,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12242,"output_tokens":4270,"usd":0.08398,"stage2_stop_reason":"end_turn"},"total_usd":0.184217,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"APELA (Elabela/Toddler) binds directly to the APJ receptor with high affinity (Kd = 0.51 nM), competes with apelin for the same binding site, and activates the inhibitory G protein (Gi) pathway by inhibiting forskolin-stimulated cAMP production and inducing ERK1/2 phosphorylation.\",\n      \"method\": \"Chimeric ligand binding assay, radioligand competition, cAMP inhibition assay, ERK1/2 phosphorylation (Western blot), in vivo diuresis/water intake studies in adult rats\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding measured by competition assay with Kd determination, Gi signaling confirmed by cAMP inhibition, ERK phosphorylation, and in vivo functional readout; multiple orthogonal methods in one study\",\n      \"pmids\": [\"25995451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"APELA binds to apelin receptors in the adult rodent heart (non-cardiomyocyte fraction), increases cardiac contractility and induces coronary vasodilation, and this inotropic effect is accompanied by ERK1/2 phosphorylation; pharmacological inhibition of ERK1/2 markedly attenuates apela-induced inotropy.\",\n      \"method\": \"Receptor binding in heart tissue, isolated adult rat heart perfusion, Western blot for ERK1/2 phosphorylation, pharmacological ERK1/2 inhibitor experiments\",\n      \"journal\": \"Basic research in cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding evidence, functional ex vivo cardiac assay, causal pathway confirmed by pharmacological inhibition, multiple methods in single lab\",\n      \"pmids\": [\"26611206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Loss of Apela in mice (CRISPR/Cas9 null allele) causes low-penetrance cardiovascular defects, vascular remodeling defects, and aberrant upregulation of erythroid and myeloid markers. Double-mutant analysis showed that Apela signaling impacts early Aplnr-expressing mesodermal populations independently of the alternative ligand Apelin, and combined loss causes lethal cardiac defects.\",\n      \"method\": \"CRISPR/Cas9 knockout, 3D micro-CT, transcriptomics (RNA-seq), double-mutant epistasis analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic null allele, multiple phenotypic readouts, epistasis with Apelin double mutant establishes pathway independence; replicated across multiple embryos\",\n      \"pmids\": [\"28854362\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Apela RNA functions as a regulatory (non-coding) RNA in mouse embryonic stem cells that interacts with hnRNPL protein, thereby preventing mitochondrial localization and activation of p53. This forms a tri-element negative feedback loop (p53 → represses Apela → Apela/hnRNPL suppresses p53 mitochondrial activation) regulating p53-mediated DNA damage-induced apoptosis. The coding ability of Apela is dispensable for this function.\",\n      \"method\": \"RNA–protein interaction (Apela RNA pulldown with hnRNPL), genetic depletion (shRNA knockdown), co-immunoprecipitation, subcellular fractionation of p53, apoptosis assay in ESCs after DNA damage\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNA–protein interaction validated by pulldown, functional rescue experiments, subcellular localization change demonstrated by fractionation, coding-null mutant confirms non-coding mechanism; multiple orthogonal methods\",\n      \"pmids\": [\"25936916\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"APELA promotes tumor cell growth and migration in ovarian clear cell carcinoma (OCCC) through an APLNR-independent pathway in cells lacking APLNR expression, and affects cell-cycle progression in a p53-dependent manner; APELA knockdown induced p53 expression.\",\n      \"method\": \"CRISPR/Cas9 APELA knockout in OCCC cell lines, recombinant APELA peptide addition, cell growth/migration assays, cell-cycle analysis, p53 expression by Western blot\",\n      \"journal\": \"Gynecologic oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR knockout with multiple cellular phenotypic readouts, APLNR-independence demonstrated by receptor expression status; single lab, limited mechanistic depth\",\n      \"pmids\": [\"29079036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The APELA precursor (proELA) is cleaved by furin to generate mature ELA; site-directed mutagenesis of the furin cleavage site improves ELA antitumorigenic activity. Mature ELA suppresses kidney tumor cell growth, migration, and survival through mTORC1 signaling activation.\",\n      \"method\": \"Site-directed mutagenesis of furin cleavage site, pharmacological furin inhibition, mTORC1 signaling assays, tumor cell growth/migration assays in vitro, xenograft mouse model with sunitinib combination\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — site-directed mutagenesis of catalytic processing site, in vitro mechanistic assays, and in vivo xenograft validation; multiple orthogonal methods in one study\",\n      \"pmids\": [\"32516140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Apela isoforms (apela-54, -32, and -11) exhibit distinct membrane-binding behaviors: apela-32 interacts with DPC, SDS, and LPPG micelles (inducing α-helical character), while apela-11 interacts preferentially with SDS and LPPG micelles (inducing β-turn character), indicating isoform- and headgroup-dependent membrane interactions that may influence apelin receptor recognition.\",\n      \"method\": \"NMR spectroscopy (pulsed-field gradient diffusion NMR, chemical shift perturbation), circular dichroism (CD) spectropolarimetry\",\n      \"journal\": \"Biochimica et biophysica acta. Biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — rigorous biophysical NMR and CD methods but functional consequence for receptor binding inferred rather than directly demonstrated; single lab\",\n      \"pmids\": [\"28132903\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Apela inhibits angiotensin II-induced inflammatory responses in renal glomerular endothelial cells (including MCP-1, TNF-α, ICAM-1, VCAM-1 expression and THP-1 cell adhesion) by inhibiting the NFκB signaling pathway; blockade of the APJ receptor abolishes these inhibitory effects, confirming APJ-dependence.\",\n      \"method\": \"In vitro cell treatment (RGECs), Western blot for phospho-NFκB, cytokine measurement, APJ inhibitor (pharmacological blockade), THP-1 adhesion assay; in vivo CRS mouse model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — APJ dependence confirmed by pharmacological antagonism, NFκB pathway implicated by phosphorylation Western blot, multiple readouts in single lab\",\n      \"pmids\": [\"34516679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELA-11 (the furin-cleaved 11-residue fragment of APELA) protects cardiomyocytes against oxidative stress-induced apoptosis through PI3K/AKT and ERK/MAPK signaling pathways, and its protective effect is mediated through the APJ receptor (blocked by ML221, an APJ antagonist).\",\n      \"method\": \"In vivo DOX-injured mouse model, in vitro cardiomyocyte assays with DOX and CoCl2, Western blot for PI3K/AKT and ERK/MAPK, pharmacological APJ antagonist (ML221) blocking experiment\",\n      \"journal\": \"Frontiers in pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — APJ receptor dependency confirmed by pharmacological antagonism, signaling pathway confirmed by Western blot, in vivo and in vitro concordant results; single lab\",\n      \"pmids\": [\"36160397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ELABELA improves endothelial cell function (viability, migration, tube formation) via the ELA–APJ axis by activating PI3K/Akt signaling; the PI3K inhibitor wortmannin blocks ELA-induced effects and also blocks ELA-induced APJ receptor upregulation.\",\n      \"method\": \"HUVEC and EA.hy926 cell treatment, CCK-8 viability, scratch-wound, tube formation assays, Western blot for PI3K/Akt, pharmacological PI3K inhibition (wortmannin)\",\n      \"journal\": \"Clinical and experimental pharmacology & physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PI3K/Akt pathway confirmed by pharmacological inhibition with functional readouts; single lab, two cell lines\",\n      \"pmids\": [\"32687618\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In non-mammalian vertebrates (zebrafish, spotted gar, pigeon), APELA peptides activate GPR25 (an orphan GPCR) to inhibit cAMP production and induce receptor internalization; human GPR25 was NOT activated by Apela under the same conditions.\",\n      \"method\": \"pGL3-CRE-luciferase reporter assay for cAMP inhibition, confocal microscopy for receptor internalization, heterologous expression in HEK293 cells\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay with multiple non-mammalian orthologs, negative result for human GPR25 explicitly documented; single lab\",\n      \"pmids\": [\"29727602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELA-32 (Apela) in human plasma has a half-life of ~47 min and in kidney homogenates ~44 s. The primary metabolic fragments generated include ELA-11, ELA-16, ELA-19, and ELA-20; ELA-16 was identified as a potentially more stable fragment.\",\n      \"method\": \"LC-MS/MS (Orbitrap) metabolic stability assay in human plasma and kidney homogenates, PEAKS Studio peptide fragment analysis\",\n      \"journal\": \"Peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous LC-MS/MS identification of metabolites with defined half-life values; single lab but well-controlled in vitro biochemistry\",\n      \"pmids\": [\"34455010\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Apela gene therapy (AAV-ELA32) in monocrotaline-induced pulmonary arterial hypertension rats upregulates KLF2/eNOS and BMPRII/SMAD4 signaling in pulmonary arterioles, inhibits endothelial-to-mesenchymal transition, and reduces pulmonary arteriolar muscularization.\",\n      \"method\": \"AAV-mediated gene delivery, right ventricular systolic pressure measurement, histopathology, immunofluorescence, Western blotting for KLF2/eNOS and BMPRII/SMAD4\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene therapy model with defined molecular pathway readouts; single lab, multiple signaling endpoints measured\",\n      \"pmids\": [\"35747913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Two rare variants in the 5'-UTR of the APELA gene (c.-306A>G and c.-145A>G) impair transcriptional activity of APELA by altering promoter function, as demonstrated by luciferase reporter assays in HEK293 and HTR-8/SVneo cells.\",\n      \"method\": \"Sanger sequencing, luciferase reporter assay in HEK293 and HTR-8/SVneo cells\",\n      \"journal\": \"Prenatal diagnosis\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single functional assay (luciferase) in cell lines; no protein-level or in vivo validation; single lab\",\n      \"pmids\": [\"30719741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish fin regeneration, Apela selectively accumulates in newly formed fin tissue and vessels; morpholino-mediated knockdown of Apela prevents vessel remodeling, while exogenous Apela peptide mediates plexus repression and promotes arterial development in regenerated fins. Apela also regulates expression of vascular remodeling genes including VWF, IGFBP3, ESM1, VEGFR2, Apln, and Aplnr.\",\n      \"method\": \"In vivo fin regeneration model in zebrafish, morpholino knockdown, exogenous peptide rescue, gene expression analysis\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino loss-of-function with rescue by exogenous peptide in zebrafish in vivo model; single lab but orthogonal loss-of-function and gain-of-function\",\n      \"pmids\": [\"38355946\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELA-11 suppresses macrophage foam cell formation, M1 polarization, and apoptosis via inhibition of the AKT–endoplasmic reticulum (ER) stress pathway; mPEG@ELA-11 (a pH-responsive conjugate) reduces atherosclerotic plaque area more effectively than free ELA-11 in ApoE-/- mice.\",\n      \"method\": \"In vitro RAW264.7 macrophage assays (foam cell formation, polarization, apoptosis), Western blot for AKT-ER stress pathway, in vivo ApoE-/- mouse atherosclerosis model, pH-responsive release characterization\",\n      \"journal\": \"BME frontiers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro pathway mechanistic data supported by in vivo mouse model; single lab, multiple functional readouts\",\n      \"pmids\": [\"41306397\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"APELA (Elabela/Toddler/ELA) is a secreted peptide hormone that functions as a high-affinity endogenous ligand for the APJ (APLNR) G protein-coupled receptor, activating Gi signaling to inhibit cAMP production and stimulate ERK1/2 and PI3K/AKT phosphorylation; its precursor proELA is processed by furin into mature isoforms (ELA-32, ELA-11, etc.) with distinct biological activities including regulation of cardiac contractility, vascular tone, fluid homeostasis, and angiogenesis, while the APELA RNA itself also functions independently as a non-coding regulatory RNA in embryonic stem cells, where it sequesters hnRNPL to prevent mitochondrial p53 activation and thereby modulates the apoptotic response to DNA damage.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"APELA (Elabela/Toddler/ELA) is a secreted peptide hormone that serves as a high-affinity endogenous ligand for the APJ (APLNR) receptor, where it competes with apelin for the same site, activates inhibitory Gi signaling to suppress forskolin-stimulated cAMP, and drives ERK1/2 phosphorylation [#0]. Through this APJ axis it regulates cardiovascular physiology — increasing cardiac contractility and inducing coronary vasodilation in an ERK1/2-dependent manner [#1] — and genetic ablation in mice produces cardiovascular and vascular remodeling defects together with aberrant erythroid/myeloid marker expression, with epistasis showing APELA acts on early Aplnr-expressing mesoderm independently of apelin [#2]. The APELA precursor (proELA) is processed by furin into mature isoforms, and disrupting the furin cleavage site alters its biological activity [#5, #11], with distinct fragments such as ELA-11 signaling through APJ to activate PI3K/AKT and ERK/MAPK and to protect against oxidative and inflammatory stress [#8, #9]. Beyond its receptor-mediated peptide role, the APELA RNA acts independently as a non-coding regulatory transcript in embryonic stem cells, binding hnRNPL to block mitochondrial p53 localization and thereby restrain DNA-damage-induced apoptosis in a manner that does not require its coding capacity [#3]. APELA also exerts APLNR-independent, p53-linked effects on tumor cell proliferation [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established APELA as a bona fide endogenous APJ ligand, answering whether it engages the same receptor as apelin and through which G protein pathway.\",\n      \"evidence\": \"Radioligand competition with Kd determination, cAMP inhibition and ERK1/2 Western blot, plus in vivo diuresis studies in rats\",\n      \"pmids\": [\"25995451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the APELA-APJ interaction not resolved\", \"Relative contribution of individual isoforms to receptor activation not dissected\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Revealed a coding-independent function: the APELA RNA itself is a regulatory non-coding RNA controlling the p53 apoptotic response, separating the transcript's role from the peptide's.\",\n      \"evidence\": \"RNA pulldown with hnRNPL, shRNA depletion, p53 subcellular fractionation, and apoptosis assays in mouse ESCs, with a coding-null mutant\",\n      \"pmids\": [\"25936916\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of the APELA RNA-hnRNPL interaction unknown\", \"Whether this RNA function operates outside ESCs unaddressed\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated APELA's physiological cardiac role and confirmed ERK1/2 as the effector mediating its inotropic action.\",\n      \"evidence\": \"Receptor binding in heart tissue and isolated rat heart perfusion with pharmacological ERK1/2 inhibition\",\n      \"pmids\": [\"26611206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell type within heart mediating contractility not defined beyond non-cardiomyocyte fraction\", \"Chronic versus acute effects not distinguished\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Genetic loss-of-function placed APELA in early mesodermal/cardiovascular development and showed it acts independently of apelin on shared APJ-expressing populations.\",\n      \"evidence\": \"CRISPR/Cas9 null mice, micro-CT, RNA-seq, and Apelin double-mutant epistasis\",\n      \"pmids\": [\"28854362\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Basis of low penetrance unexplained\", \"Molecular driver of erythroid/myeloid dysregulation not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified an APLNR-independent, p53-linked APELA activity in cancer cells, broadening its mechanism beyond receptor signaling.\",\n      \"evidence\": \"CRISPR knockout and recombinant peptide addition in OCCC lines lacking APLNR, with cell-cycle and p53 Western blot readouts\",\n      \"pmids\": [\"29079036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The receptor or effector mediating the APLNR-independent effect unknown\", \"Direct link between APELA and p53 induction not mechanistically defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Characterized isoform-specific membrane interactions that may shape receptor recognition, providing a biophysical basis for functional differences among isoforms.\",\n      \"evidence\": \"NMR diffusion/chemical shift and CD spectropolarimetry with micelle systems\",\n      \"pmids\": [\"28132903\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence for receptor binding inferred, not directly shown\", \"Relevance to native membranes untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Mapped an alternative receptor (GPR25) for APELA in non-mammalian vertebrates while showing human GPR25 is not activated, clarifying receptor usage across species.\",\n      \"evidence\": \"CRE-luciferase cAMP reporter and receptor internalization in HEK293 cells across orthologs\",\n      \"pmids\": [\"29727602\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of GPR25 signaling in vivo unestablished\", \"Why human GPR25 is unresponsive not explained\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined furin as the maturation protease for proELA and linked processing to mTORC1-dependent anti-tumor activity, connecting precursor handling to function.\",\n      \"evidence\": \"Site-directed mutagenesis of the furin site, furin inhibition, mTORC1 assays, and kidney tumor xenografts\",\n      \"pmids\": [\"32516140\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How mature ELA engages mTORC1 mechanistically not resolved\", \"Receptor dependence of the anti-tumor effect not pinned down\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed the ELA-APJ axis promotes endothelial function via PI3K/Akt, extending APELA's vascular signaling repertoire.\",\n      \"evidence\": \"HUVEC/EA.hy926 viability, migration, tube formation with wortmannin inhibition and Western blot\",\n      \"pmids\": [\"32687618\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo angiogenic relevance not tested in this study\", \"Single-pathway focus leaves crosstalk unaddressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Determined APELA peptide metabolic stability and the fragment cascade, identifying the bioactive/stable species generated in plasma and kidney.\",\n      \"evidence\": \"LC-MS/MS metabolic stability assays in human plasma and kidney homogenates\",\n      \"pmids\": [\"34455010\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor activity of each metabolite not measured here\", \"In vivo clearance in humans not validated\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated APJ-dependent anti-inflammatory signaling via NF\\u03baB inhibition in renal endothelium, linking APELA to renoprotection.\",\n      \"evidence\": \"RGEC treatment with APJ pharmacological blockade, phospho-NF\\u03baB Western blot, cytokine and adhesion assays, plus a CRS mouse model\",\n      \"pmids\": [\"34516679\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct receptor-to-NF\\u03baB coupling mechanism not defined\", \"Single-lab in vivo confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Showed ELA-11 protects cardiomyocytes from oxidative apoptosis through APJ-dependent PI3K/AKT and ERK/MAPK signaling, defining a specific cardioprotective fragment.\",\n      \"evidence\": \"DOX-injured mouse and cardiomyocyte assays with ML221 APJ antagonist and pathway Western blots\",\n      \"pmids\": [\"36160397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Why the 11-residue fragment is preferentially active not explained\", \"Long-term cardioprotection not assessed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established a therapeutic vascular role in pulmonary hypertension via KLF2/eNOS and BMPRII/SMAD4 signaling and EndMT suppression.\",\n      \"evidence\": \"AAV-ELA32 gene therapy in monocrotaline PAH rats with hemodynamic, histologic, and Western blot readouts\",\n      \"pmids\": [\"35747913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether effects are APJ-mediated not directly tested\", \"Causal ordering of the two signaling axes unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined APELA as a regulator of vessel remodeling and arterial specification during regeneration through control of vascular gene programs.\",\n      \"evidence\": \"Zebrafish fin regeneration with morpholino knockdown and exogenous peptide rescue plus gene expression analysis\",\n      \"pmids\": [\"38355946\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct targets among the regulated genes not distinguished from indirect\", \"Receptor mediating regenerative effect not specified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended ELA-11's anti-inflammatory action to atherosclerosis via AKT-ER stress inhibition in macrophages, with a delivery strategy improving efficacy.\",\n      \"evidence\": \"RAW264.7 macrophage assays, AKT-ER stress Western blots, and an mPEG@ELA-11 conjugate in ApoE-/- mice\",\n      \"pmids\": [\"41306397\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor mediating the macrophage effect not established\", \"Mechanistic link between AKT and ER stress not fully resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How APELA's two distinct modes — secreted APJ-ligand peptide signaling and coding-independent RNA regulation of p53 — are coordinated within a single cell, and the identity of the receptor(s) mediating its multiple APLNR-independent activities, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking RNA and peptide functions\", \"APLNR-independent receptor(s) unidentified\", \"No structural model of APELA-receptor or APELA-hnRNPL complexes\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 1, 8]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 10]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 5, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 8, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [2, 14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [3, 8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"APLNR\",\n      \"hnRNPL\",\n      \"FURIN\",\n      \"GPR25\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}