Abstract
Introduction
Elabela is a newly identified peptide which, alongside apelin, acts as an endogenous ligand that activates the angiotensin receptor-like 1 receptor. Previous studies have shown the association of elabela with hypertension, but information about the role of elabela in hypertension-related subclinical atherosclerosis is scarce.
Aim
We aimed to determine the elabela levels in hypertensive patients and explore its association with subclinical atherosclerosis.
Methods
A total of 104 subjects with hypertension were included in the study. Elabela levels were measured using an enzyme-linked immunosorbent assay, by first extracting the peptide following the manufacturer's instructions. Subclinical atherosclerosis was assessed by measuring the carotid intima-media thickness (IMT) using ultrasound.
Results
Compared to stage 1, elabela levels decreased in stage 2 hypertension (0.23 [0.13, 0.45] ng/ml vs. 0.14 [0.09, 0.23] ng/ml; P = 0.000), and in the group with increased carotid IMT compared to normal IMT (0.24 [0.13, 0.38] ng/ml vs. 0.15 [0.10, 0.23] ng/ml; P = 0.005). Additionally, a linear correlation analysis showed that elabela had a significant negative correlation with systolic blood pressure (r = − 0.340, P = 0.000) and carotid IMT (r = − 0.213; P = 0.030). In multivariate analysis, lower elabela levels were associated with a higher cardiovascular risk group in this study (OR 5.0, 95% CI 1.8–13.5, P < 0.001).
Conclusions
This study demonstrated for the first time that circulating elabela declined in a higher stage of hypertension and hypertensive patients with increased carotid IMT, implicating that elabela may be involved in the pathogenesis of hypertension-associated subclinical atherosclerosis.
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References
Corrigendum to: 2018 ESC/ESH guidelines for the management of arterial hypertension. Eur Heart J. 2018;40(5):475. https://doi.org/10.1093/eurheartj/ehy686.
Hall ME, Hall JE. 5—pathogenesis of hypertension. In: Bakris GL, Sorrentino MJ, editors. Hypertension: a companion to Braunwald’s heart disease. 3rd ed. Amsterdam: Elsevier; 2018. p. 33–51.
Hong YM. Atherosclerotic cardiovascular disease beginning in childhood. Korean Circ J. 2010;40(1):1–9. https://doi.org/10.4070/kcj.2010.40.1.1.
Simova I. Intima-media thickness: appropriate evaluation and proper measurement. e-J Cardiol Pract. 2015;13(21).
Polak JF, O’Leary DH. Carotid intima-media thickness as surrogate for and predictor of CVD. Glob Heart. 2016;11(3):295-312.e3. https://doi.org/10.1016/j.gheart.2016.08.006.
Papageorgiou N, Briasoulis A, Androulakis E, Tousoulis D. Imaging subclinical atherosclerosis: where do we stand? Curr Cardiol Rev. 2017;13(1):47–55. https://doi.org/10.2174/1573403x12666160803095855.
Chng Serene C, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6):672–80. https://doi.org/10.1016/j.devcel.2013.11.002.
Pauli A, Norris ML, Valen E, Chew G-L, Gagnon JA, Zimmerman S, et al. Toddler: an embryonic signal that promotes cell movement via apelin receptors. Science. 2014;343(6172):1248636. https://doi.org/10.1126/science.1248636.
Kuba K, Sato T, Imai Y, Yamaguchi T. Apelin and elabela/toddler; double ligands for APJ/apelin receptor in heart development, physiology, and pathology. Peptides. 2019;111:62–70. https://doi.org/10.1016/j.peptides.2018.04.011.
Xu J, Chen L, Jiang Z, Li L. Biological functions of elabela, a novel endogenous ligand of APJ receptor. J Cell Physiol. 2018;233(9):6472–82. https://doi.org/10.1002/jcp.26492.
Xu C. The elabela in hypertension, cardiovascular disease, renal disease, and preeclampsia: an update. J Hypertens. 2021;39(1):12–22. https://doi.org/10.1097/hjh.0000000000002591.
Diakowska D, Wyderka R, Krzystek-Korpacka M, Osuch Ł, Leśków A, Sołtowska A, et al. Plasma levels of apelinergic system components in patients with chronic and acute coronary syndromes—a pilot study. J Clin Med. 2021. https://doi.org/10.3390/jcm10194420.
Dindas F, Koyuncu I, Ocek L, Ozdemir AV, Yılmaz H, Abacıoglu OO, et al. Association of serum elabela levels with carotid artery stenosis in patients with non-cardioembolic ischemic stroke. Biomark Med. 2022;16(8):623–31. https://doi.org/10.2217/bmm-2021-0865.
Ferreira JP, Girerd N, Bozec E, Machu JL, Boivin JM, London GM, et al. Intima-media thickness is linearly and continuously associated with systolic blood pressure in a population-based cohort (STANISLAS cohort study). J Am Heart Assoc. 2016. https://doi.org/10.1161/jaha.116.003529.
Touboul PJ, Hennerici MG, Meairs S, Adams H, Amarenco P, Bornstein N, et al. Mannheim carotid intima-media thickness and plaque consensus (2004–2006–2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis. 2012;34(4):290–6. https://doi.org/10.1159/000343145.
Chng SC, Ho L, Tian J, Reversade B. ELABELA: a hormone essential for heart development signals via the apelin receptor. Dev Cell. 2013;27(6):672–80. https://doi.org/10.1016/j.devcel.2013.11.002.
Zhang Y, Wang Y, Lou Y, Luo M, Lu Y, Li Z, et al. Elabela, a newly discovered APJ ligand: similarities and differences with apelin. Peptides. 2018;109:23–32. https://doi.org/10.1016/j.peptides.2018.09.006.
Murza A, Trân K, Bruneau-Cossette L, Lesur O, Auger-Messier M, Lavigne P, et al. Apelins, ELABELA, and their derivatives: peptidic regulators of the cardiovascular system and beyond. Pept Sci. 2019;111(1): e24064. https://doi.org/10.1002/pep2.24064.
Sato T, Sato C, Kadowaki A, Watanabe H, Ho L, Ishida J, et al. ELABELA-APJ axis protects from pressure overload heart failure and angiotensin II-induced cardiac damage. Cardiovasc Res. 2017;113(7):760–9. https://doi.org/10.1093/cvr/cvx061.
Wang Z, Yu D, Wang M, Wang Q, Kouznetsova J, Yang R, et al. Elabela-apelin receptor signaling pathway is functional in mammalian systems. Sci Rep. 2015;5:8170. https://doi.org/10.1038/srep08170.
Yang P, Maguire JJ, Davenport AP. Apelin, elabela/toddler, and biased agonists as novel therapeutic agents in the cardiovascular system. Trends Pharmacol Sci. 2015;36(9):560–7. https://doi.org/10.1016/j.tips.2015.06.002.
Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16(4):223–37. https://doi.org/10.1038/s41581-019-0244-2.
Li Y, Yang X, Ouyang S, He J, Yu B, Lin X, et al. Declined circulating elabela levels in patients with essential hypertension and its association with impaired vascular function: a preliminary study. Clin Exp Hypertens. 2020;42(3):239–43. https://doi.org/10.1080/10641963.2019.1619756.
Mughal A, O’Rourke ST. Vascular effects of apelin: mechanisms and therapeutic potential. Pharmacol Ther. 2018;190:139–47. https://doi.org/10.1016/j.pharmthera.2018.05.013.
Chun HJ, Ali ZA, Kojima Y, Kundu RK, Sheikh AY, Agrawal R, et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J Clin Investig. 2008;118(10):3343–54. https://doi.org/10.1172/JCI34871.
Zhang Y, Wang Y, Luo M, Xu F, Lu Y, Zhou X, et al. Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway. Peptides. 2019;114:29–37. https://doi.org/10.1016/j.peptides.2019.04.005.
Mancini GBJ. Carotid intima-media thickness as a measure of vascular target organ damage. Curr Hypertens Rep. 2000;2(1):71–7. https://doi.org/10.1007/s11906-000-0062-7.
Kaligis RW, Adiarto S, Nugroho J, Pradnyana BA, Lefi A, Rifqi S. Carotid intima-media thickness in Indonesian subjects with cardiovascular disease risk factors who were not receiving lipid-lowering agents. Int J Angiol. 2016;25(3):174–80. https://doi.org/10.1055/s-0036-1572365.
Øygarden H. Carotid intima-media thickness and prediction of cardiovascular disease. J Am Heart Assoc. 2017;6(1): e005313. https://doi.org/10.1161/JAHA.116.005313.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–89. https://doi.org/10.1056/NEJMoa0806470.
Liu W, Yan J, Pan W, Tang M. Apelin/elabela-APJ: a novel therapeutic target in the cardiovascular system. Ann Transl Med. 2020;8(5):243. https://doi.org/10.21037/atm.2020.02.07.
Huang Z, He L, Chen Z, Chen L. Targeting drugs to APJ receptor: from signaling to pathophysiological effects. J Cell Physiol. 2018;234(1):61–74. https://doi.org/10.1002/jcp.27047.
Kadoglou NPE, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Kostakis A, et al. Adipokines: a novel link between adiposity and carotid plaque vulnerability. Eur J Clin Invest. 2012;42(12):1278–86. https://doi.org/10.1111/j.1365-2362.2012.02728.x.
Mortazavi A, Nematipoor E, Djalali M, Keshavarz SA, Samavat S, Zarei M, et al. The effect of Omega-3 fatty acids on serum apelin levels in cardiovascular disease: a randomized, double-blind, placebo-controlled trial. Rep Biochem Mol Biol. 2018;7(1):59–66.
Acknowledgements
The authors wish to acknowledge the help provided by the Natuna Regency Government and the Indonesian Medical Association Natuna branch in data collection. We would also like to show our deep appreciation to the technical and support staff in the Cardiovascular Research and Development Division of the National Cardiovascular Center Harapan Kita who provided valuable expertise in sample preparation, protein extraction, and elabela ELISA quantification.
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All the authors declare no conflict of interest.
Disclosures
This study has been presented in the 16th Annual Scientific Meeting of the Indonesian Society of Hypertension and published as an abstract accordingly in the Journal of Hypertension Supplements May 2022—Volume 40—Issue Suppl 2—p e3.
Funding
This work was funded by the National Cardiovascular Center Harapan Kita, Jakarta, Indonesia (Grant no. HK.02.03/XX.4/0165/2020).
Ethical approval
The study was approved by the local IRB with protocol no. LB.02.01/VII/499/KEP081/2020.
Data Availability Statement
The data used to support the findings of this study are available from the first author upon reasonable request.
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Hendrianus, Adiarto, S., Prakoso, R. et al. A Novel Peptide Elabela is Associated with Hypertension-Related Subclinical Atherosclerosis. High Blood Press Cardiovasc Prev 30, 37–44 (2023). https://doi.org/10.1007/s40292-022-00554-1
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DOI: https://doi.org/10.1007/s40292-022-00554-1