Elabela

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.[3]

APELA
Identifiers
AliasesAPELA, ELA, Ende, tdl, apelin receptor early endogenous ligand
External IDsOMIM: 615594 GeneCards: APELA
Orthologs
SpeciesHumanMouse
Entrez

100506013

n/a

Ensembl

ENSG00000248329

n/a

UniProt

P0DMC3

n/a

RefSeq (mRNA)

NM_001297550

n/a

RefSeq (protein)

NP_001284479

n/a

Location (UCSC)Chr 4: 164.88 – 164.9 Mbn/a
PubMed search[2]n/a
Wikidata
View/Edit Human

Ela is secreted by certain cell types including human embryonic stem cells.[4] It is widely expressed in various developing organs such as the blastocyst,[5] placenta,[6] heart,[7] kidney,[8] endothelium, and is circulating in human plasma.

Discovery

Elabela is a micropeptide that was identified in 2013 by Professor Bruno Reversade's team.[5]

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.[9]

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[4] and certain cancer cell lines including OVISE.[10]

Embryonic pluripotency

The Elabela protein is synthesized, processed and secreted by undifferentiated human embryonic stem cells [5] 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.[4]

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.[11] This participates in the formation of the first and secondary vessels of the vascular system.[12]

Cardiac

The ELABELA -APLNR signaling axis is required for formation of the coronary vessels of the heart in mice through the sinus venosus progenitors.[13]

Pre-eclampsia
See also: Pre-eclampsia

ELA is a secreted into the bloodstream by the developing placenta. Pregnant mice lacking Ela,[14] exhibit pre-eclampsia-like symptoms, characterized by proteinuria and gestational hypertension.[6]

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.[15]

Therapeutics

Several mimetics of ELA have been developed for therapeutic purposes. Amgen has created a camel antibody[16] and a small molecule[17] 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.[18]

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.[19]

References
  1. GRCh38: Ensembl release 89: ENSG00000248329 - Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
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