Elabela Explained

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.[1]

Ela is secreted by certain cell types including human embryonic stem cells.[2] It is widely expressed in various developing organs such as the blastocyst,[3] placenta,[4] heart,[5] kidney,[6] endothelium, and is circulating in human plasma.

Discovery

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

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.[7]

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 and certain cancer cell lines including OVISE.[8]

Embryonic pluripotency

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

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.[9] This participates in the formation of the first and secondary vessels of the vascular system.[10]

Cardiac

The ELABELA -APLNR signaling axis is required for formation of the coronary vessels of the heart in mice through the sinus venosus progenitors.[11]

Pre-eclampsia

ELA is a secreted into the bloodstream by the developing placenta. Pregnant mice lacking Ela,[12] exhibit pre-eclampsia-like symptoms, characterized by proteinuria and gestational hypertension.

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.[13]

Therapeutics

Several mimetics of ELA have been developed for therapeutic purposes. Amgen has created a camel antibody[14] and a small molecule[15] 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.[16]

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.[17]

Notes and References

  1. Read C, Nyimanu D, Williams TL, Huggins DJ, Sulentic P, Macrae RG, Yang P, Glen RC, Maguire JJ, Davenport AP . 6 . 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 . October 2019 . 31492821 . 6731456 . 10.1124/pr.119.017533 . Ohlstein EH .
  2. Ho L, Tan SY, Wee S, Wu Y, Tan SJ, Ramakrishna NB, Chng SC, Nama S, Szczerbinska I, Sczerbinska I, Chan YS, Avery S, Tsuneyoshi N, Ng HH, Gunaratne J, Dunn NR, Reversade B . 6 . ELABELA Is an Endogenous Growth Factor that Sustains hESC Self-Renewal via the PI3K/AKT Pathway . Cell Stem Cell . 17 . 4 . 435–47 . October 2015 . 26387754 . 10.1016/j.stem.2015.08.010 . free .
  3. Chng SC, Ho L, Tian J, Reversade B . ELABELA: a hormone essential for heart development signals via the apelin receptor . Developmental Cell . 27 . 6 . 672–80 . December 2013 . 24316148 . 10.1016/j.devcel.2013.11.002 . free .
  4. Ho L, van Dijk M, Chye ST, Messerschmidt DM, Chng SC, Ong S, Yi LK, Boussata S, Goh GH, Afink GB, Lim CY, Dunn NR, Solter D, Knowles BB, Reversade B . 6 . ELABELA deficiency promotes preeclampsia and cardiovascular malformations in mice . Science . 357 . 6352 . 707–713 . August 2017 . 28663440 . 10.1126/science.aam6607 . 2017Sci...357..707H . 3241807 . free .
  5. Sharma B, Ho L, Ford GH, Chen HI, Goldstone AB, Woo YJ, Quertermous T, Reversade B, Red-Horse K . 6 . Alternative Progenitor Cells Compensate to Rebuild the Coronary Vasculature in Elabela- and Apj-Deficient Hearts . Developmental Cell . 42 . 6 . 655–666.e3 . September 2017 . 28890073 . 5895086 . 10.1016/j.devcel.2017.08.008 .
  6. Xu C, Wang F, Chen Y, Xie S, Sng D, Reversade B, Yang T . 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 . May 2020 . 32174138 . 7294342 . 10.1152/ajprenal.00606.2019 .
  7. Murza A, Sainsily X, Coquerel D, Côté J, Marx P, Besserer-Offroy É, Longpré JM, Lainé J, Reversade B, Salvail D, Leduc R, Dumaine R, Lesur O, Auger-Messier M, Sarret P, Marsault É . 6 . 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 . April 2016 . 26986036 . 10.1021/acs.jmedchem.5b01549 .
  8. Yi Y, Tsai SH, Cheng JC, Wang EY, Anglesio MS, Cochrane DR, Fuller M, Gibb EA, Wei W, Huntsman DG, Karsan A, Hoodless PA . 6 . APELA promotes tumour growth and cell migration in ovarian cancer in a p53-dependent manner . Gynecologic Oncology . 147 . 3 . 663–671 . December 2017 . 29079036 . 10.1016/j.ygyno.2017.10.016 .
  9. Helker CS, Schuermann A, Pollmann C, Chng SC, Kiefer F, Reversade B, Herzog W . The hormonal peptide Elabela guides angioblasts to the midline during vasculogenesis . eLife . 4 . e06726 . May 2015 . 26017639 . 4468421 . 10.7554/eLife.06726 . free .
  10. Helker CS, Eberlein J, Wilhelm K, Sugino T, Malchow J, Schuermann A, Baumeister S, Kwon HB, Maischein HM, Potente M, Herzog W, Stainier DY . 6 . Apelin signaling drives vascular endothelial cells toward a pro-angiogenic state . eLife . 9 . e55589 . September 2020 . 32955436 . 7567607 . 10.7554/eLife.55589 . free .
  11. 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. 10.1016/j.devcel.2017.08.008. 1878-1551. 5895086. 28890073.
  12. Papangeli I, Chun HJ . A Tale of Two Elabela Null Mice . Trends in Endocrinology and Metabolism . 28 . 11 . 759–760 . November 2017 . 28964631 . 5673578 . 10.1016/j.tem.2017.09.004 .
  13. Xu C . The Elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update . Journal of Hypertension . 39 . 1 . 12–22 . January 2021 . 32740407 . 10.1097/HJH.0000000000002591 . 220944866 .
  14. 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. en. 6. 3. eaax7379. 10.1126/sciadv.aax7379. 2375-2548. 6962038. 31998837. 2020SciA....6.7379M.
  15. 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. 10.1172/jci.insight.132898. 2379-3708. 7205427. 32208384.
  16. 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. 10.1016/j.bmcl.2020.126955. 1464-3405. 32035698. 211071546 .
  17. Hassan. Sonia S.. Gomez-Lopez. Nardhy. 2019-07-06. Reducing maternal mortality: can elabela help in this fight?. Lancet. 394. 10192. 8–9. 10.1016/S0140-6736(19)30543-4. 1474-547X. 31282362. 195829649.

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