Elabela

APELA
Identifiers
Aliases	APELA , ELA, Ende, tdl, apelin receptor early endogenous ligand
External IDs	OMIM: 615594; MGI: 3642370; GeneCards: APELA; OMA:APELA - orthologs
Gene location (Human) Chr. Chromosome 4 (human) [1] Band 4q32.3 Start 164,877,178 bp [1] End 164,898,965 bp [1]
Gene location (Mouse) Chr. Chromosome 8 (mouse) [2] Band 8 B3.1|8 Start 65,481,069 bp [2] End 65,489,988 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in tibia testicle buccal mucosa cell mucosa of paranasal sinus palpebral conjunctiva olfactory zone of nasal mucosa prostate skin of abdomen placenta skin of hip Top expressed in medullary collecting duct tail of embryo primitive streak endocardial cushion right kidney human kidney atrioventricular valve definitive endoderm embryo hand More reference expression data BioGPS n/a
Gene ontology Molecular function hormone activity apelin receptor binding Cellular component extracellular region extracellular space Biological process multicellular organism development mesendoderm migration cell migration involved in mesendoderm migration endoderm development gastrulation heart development SMAD protein signal transduction positive regulation of angiogenesis apelin receptor signaling pathway positive regulation of G protein-coupled receptor internalization regulation of signaling receptor activity vasculogenesis mesoderm migration involved in gastrulation adult heart development embryonic heart tube development positive regulation of heart contraction placenta blood vessel development coronary vasculature development positive regulation of ERK1 and ERK2 cascade positive regulation of trophoblast cell migration positive regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis angiogenesis cell differentiation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 100506013 100038489 Ensembl ENSG00000248329 ENSMUSG00000079042 UniProt P0DMC3 P0DMC4 RefSeq (mRNA) NM_001297550 NM_001297554 NM_001399422 RefSeq (protein) NP_001284479 NP_001284483 NP_001386351 Location (UCSC) Chr 4: 164.88 – 164.9 Mb Chr 8: 65.48 – 65.49 Mb PubMed search [3] [4]
Wikidata
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ELABELA (ELA, Apela, Toddler) is a hormonal peptide that in humans is encoded by the APELA gene. Elabela is one of two endogenous ligands for the G-protein-coupled APLNR receptor. ^[5]

Ela is secreted by certain cell types including human embryonic stem cells. ^[6] It is widely expressed in various developing organs such as the blastocyst, ^[7] placenta, ^[8] heart, ^[9] kidney, ^[10] endothelium, and is circulating in human plasma.

Discovery

Elabela is a micropeptide that was identified in 2013 by Professor Bruno Reversade's team. ^[7]

Biosynthesis

Elabela gene encodes a pre-proprotein of 54 amino acids, with a signal peptide in the N-terminal region. After translocation into the endoplasmic reticulum and cleavage of the signal peptide, the proprotein of 32 amino acids may generate several active fragments. ^[11]

Physiological functions

The sites of APLNR receptor expression are linked to the different functions played by Elabela in the organism. Despite that, Elabela is capable of signaling independently of APLNR in human embryonic stem cells ^[6] and certain cancer cell lines including OVISE. ^[12]

Embryonic pluripotency

The Elabela protein is synthesized, processed and secreted by undifferentiated human embryonic stem cells ^[7] but not mouse embryonic stem cells. In humans it is under the direct regulation of POU5F1 (a.k.a. OCT4) and NANOG.

Through autocrine and paracrine signalling, endogenous Elabela entrains the PI3K/AKT/mTOR pathway to maintain pluripotency and self-renewal. ^[6]

Vascular

Elabela is expressed by midline tissues (such as the notochord in zebrafish and neural tube in mammals) during organogenesis.

There it serves as a chemoattractant to angioblasts expressing APLNR at their cell surface. ^[13] This participates in the formation of the first and secondary vessels of the vascular system. ^[14]

Cardiac

The ELABELA -APLNR signaling axis is required for formation of the coronary vessels of the heart in mice through the sinus venosus progenitors. ^[15]

Pre-eclampsia

See also: Pre-eclampsia

ELA is a secreted into the bloodstream by the developing placenta. Pregnant mice lacking Ela, ^[16] exhibit pre-eclampsia-like symptoms, characterized by proteinuria and gestational hypertension. ^[8]

Infusion of exogenous ELA normalizes blood pressure and prevents intrauterine growth retardation in pups born to Ela knockout mothers. ELA increases the invasiveness of trophoblast-like cells, suggesting that it may enhance placental development to prevent eclampsia. ^[17]

Therapeutics

Several mimetics of ELA have been developed for therapeutic purposes. Amgen has created a camel antibody ^[18] and a small molecule ^[19] agonist capable of mimicking the function of ELA towards it cognate receptor APLNR.

The latter has entered phase 1 clinical trials for heart failure and acute kidney disease. Bristol Myers Squibb has also created its own small molecule agonist of APLNR. ^[20]

An opinion published in the Lancet in 2019 suggested that ELABELA could be used to treat intrauterine growth restriction and maternal morbidity linked to eclampsia. ^[21]

References

1. GRCh38: Ensembl release 89: ENSG00000248329 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000079042 – Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Read C, Nyimanu D, Williams TL, Huggins DJ, Sulentic P, Macrae RG, et al. (October 2019). Ohlstein EH (ed.). "International Union of Basic and Clinical Pharmacology. CVII. Structure and Pharmacology of the Apelin Receptor with a Recommendation that Elabela/Toddler Is a Second Endogenous Peptide Ligand". Pharmacological Reviews. 71 (4): 467–502. doi:10.1124/pr.119.017533. PMC   6731456 . PMID   31492821.
6. Ho L, Tan SY, Wee S, Wu Y, Tan SJ, Ramakrishna NB, et al. (October 2015). "ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway". Cell Stem Cell. 17 (4): 435–47. doi: 10.1016/j.stem.2015.08.010 . PMID   26387754.
7. Chng SC, Ho L, Tian J, Reversade B (December 2013). "ELABELA: a hormone essential for heart development signals via the apelin receptor". Developmental Cell. 27 (6): 672–80. doi: 10.1016/j.devcel.2013.11.002 . PMID   24316148.
8. Ho L, van Dijk M, Chye ST, Messerschmidt DM, Chng SC, Ong S, et al. (August 2017). "ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice". Science. 357 (6352): 707–713. Bibcode:2017Sci...357..707H. doi: 10.1126/science.aam6607 . PMID   28663440. S2CID   3241807.
9. Sharma B, Ho L, Ford GH, Chen HI, Goldstone AB, Woo YJ, et al. (September 2017). "Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts". Developmental Cell. 42 (6): 655–666.e3. doi:10.1016/j.devcel.2017.08.008. PMC   5895086 . PMID   28890073.
10. Xu C, Wang F, Chen Y, Xie S, Sng D, Reversade B, Yang T (May 2020). "ELABELA antagonizes intrarenal renin-angiotensin system to lower blood pressure and protects against renal injury". American Journal of Physiology. Renal Physiology. 318 (5): F1122 –F1135. doi:10.1152/ajprenal.00606.2019. PMC   7294342 . PMID   32174138.
11. Murza A, Sainsily X, Coquerel D, Côté J, Marx P, Besserer-Offroy É, et al. (April 2016). "Discovery and Structure-Activity Relationship of a Bioactive Fragment of ELABELA that Modulates Vascular and Cardiac Functions". Journal of Medicinal Chemistry. 59 (7): 2962–72. doi:10.1021/acs.jmedchem.5b01549. PMID   26986036.
12. Yi Y, Tsai SH, Cheng JC, Wang EY, Anglesio MS, Cochrane DR, et al. (December 2017). "APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner". Gynecologic Oncology. 147 (3): 663–671. doi:10.1016/j.ygyno.2017.10.016. PMID   29079036.
13. Helker CS, Schuermann A, Pollmann C, Chng SC, Kiefer F, Reversade B, Herzog W (May 2015). "The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis". eLife. 4: e06726. doi: 10.7554/eLife.06726 . PMC   4468421 . PMID   26017639.
14. Helker CS, Eberlein J, Wilhelm K, Sugino T, Malchow J, Schuermann A, et al. (September 2020). "Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state". eLife. 9: e55589. doi: 10.7554/eLife.55589 . PMC   7567607 . PMID   32955436.
15. Sharma, Bikram; Ho, Lena; Ford, Gretchen Hazel; Chen, Heidi I.; Goldstone, Andrew B.; Woo, Y. Joseph; Quertermous, Thomas; Reversade, Bruno; Red-Horse, Kristy (2017-09-25). "Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts". Developmental Cell. 42 (6): 655–666.e3. doi:10.1016/j.devcel.2017.08.008. ISSN   1878-1551. PMC   5895086 . PMID   28890073.
16. Papangeli I, Chun HJ (November 2017). "A Tale of Two Elabela Null Mice". Trends in Endocrinology and Metabolism. 28 (11): 759–760. doi:10.1016/j.tem.2017.09.004. PMC   5673578 . PMID   28964631.
17. Xu C (January 2021). "The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update". Journal of Hypertension. 39 (1): 12–22. doi:10.1097/HJH.0000000000002591. PMID   32740407. S2CID   220944866.
18. Ma, Yanbin; Ding, Yao; Song, Xianqiang; Ma, Xiaochuan; Li, Xun; Zhang, Ning; Song, Yunpeng; Sun, Yaping; Shen, Yuqing; Zhong, Wenge; Hu, Liaoyuan A. (January 2020). "Structure-guided discovery of a single-domain antibody agonist against human apelin receptor". Science Advances. 6 (3): eaax7379. Bibcode:2020SciA....6.7379M. doi:10.1126/sciadv.aax7379. ISSN   2375-2548. PMC   6962038 . PMID   31998837.
19. Ason, Brandon; Chen, Yinhong; Guo, Qi; Hoagland, Kimberly M.; Chui, Ray W.; Fielden, Mark; Sutherland, Weston; Chen, Rhonda; Zhang, Ying; Mihardja, Shirley; Ma, Xiaochuan (2020-04-23). "Cardiovascular response to small-molecule APJ activation". JCI Insight. 5 (8). doi:10.1172/jci.insight.132898. ISSN   2379-3708. PMC   7205427 . PMID   32208384.
20. Myers, Michael C.; Bilder, Donna M.; Cavallaro, Cullen L.; Chao, Hannguang J.; Su, Shun; Burford, Neil T.; Nayeem, Akbar; Wang, Tao; Yan, Mujing; Langish, Robert A.; Dabros, Marta (2020-04-01). "Discovery and SAR of aryl hydroxy pyrimidinones as potent small molecule agonists of the GPCR APJ". Bioorganic & Medicinal Chemistry Letters. 30 (7): 126955. doi:10.1016/j.bmcl.2020.126955. ISSN   1464-3405. PMID   32035698. S2CID   211071546.
21. Hassan, Sonia S.; Gomez-Lopez, Nardhy (2019-07-06). "Reducing maternal mortality: can elabela help in this fight?". Lancet. 394 (10192): 8–9. doi:10.1016/S0140-6736(19)30543-4. ISSN   1474-547X. PMID   31282362. S2CID   195829649.