Endothelin Explained

Hgncid:3176
Entrezgene:1906
Omim:131240
Refseq:NM_001955
Uniprot:P05305
Chromosome:6
Arm:p
Band:23
Locussupplementarydata:-p24
Endothelin 2
Symbol:EDN2
Entrezgene:1907
Hgncid:3177
Omim:131241
Refseq:NM_001956
Uniprot:P20800
Chromosome:1
Arm:p
Band:34
Endothelin 3
Symbol:EDN3
Hgncid:3178
Omim:131242
Refseq:NM_000114
Uniprot:P14138
Chromosome:20
Arm:q
Band:13.2
Locussupplementarydata:-q13.3

Endothelins are peptides with receptors and effects in many body organs.[1] [2] [3] Endothelin constricts blood vessels and raises blood pressure. The endothelins are normally kept in balance by other mechanisms, but when overexpressed, they contribute to high blood pressure (hypertension), heart disease, and potentially other diseases.[1] [4]

Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. Endothelins are implicated in vascular diseases of several organ systems, including the heart, lungs, kidneys, and brain.[5] [6] As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems.[1] [7] [8] [9]

Etymology

Endothelins derived the name from their isolation in cultured endothelial cells.[1] [10]

Isoforms

There are three isoforms of the peptide (identified as ET-1, 2, 3), each encoded by a separate gene, with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[1] [11]

The human genes for endothelin-1 (ET-1), endothelin-2 (ET-2), and endothelin-3 (ET-3) are located on chromosomes 6, 1, and 20, respectively.[2]

Mechanism of action and function

Endothelin functions through activation of two G protein-coupled receptors, endothelinA and endothelinB receptor (ETA and ETB, respectively).[2] These two subtypes of endothelin receptor are distinguished in the laboratory by the order of their affinity for the three endothelin peptides: the ETA receptor is selective for ET-1, whereas the ETB receptor has the same affinity for all three ET peptides.[2] The two types of ET receptor are distributed across diverse cells and organs, but with different levels of expression and activity, indicating a multiple-organ ET system.[2] Most endothelin receptors in the human cerebral cortex (~90%) are of the ETB subtype.[12]

Endothelin-1 is the most powerful endogenous chemical affecting vascular tone across organ systems.[2] [13] Secretion of endothelin-1 from the vascular endothelium signals vasoconstriction and influences local cellular growth and survival.[13] ET-1 has been implicated in the development and progression of several cardiovascular diseases, such as atherosclerosis and hypertension.[13] Endothelin also has roles in mitogenesis, cell survival, angiogenesis, bone growth, nociceptor function, and cancer onset mechanisms.[2] Clinically, anti-ET drugs are used to treat pulmonary arterial hypertension.[2] [13]

Endothelin-2 differs from endothelin-1 by two amino acids, and sometimes has the same affinity as endothelin-1 for ETA and ETB receptors. Studies have shown that endothelin-2 plays a significant role in ovarian physiology and could impact the pathophysiology of heart failure, immunology, and cancer.[12]

Physiological effects

Endothelins are the most potent vasoconstrictors known.[1] [14] Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan.[1]

Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the three pituitary lobes[15] which display increased metabolic activity when exposed to ET-1 in the blood or ventricular system.[16]

ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension.[17] The ETA receptor for ET-1 is primarily located on vascular smooth muscle cells, mediating vasoconstriction, whereas the ETB receptor for ET-1 is primarily located on endothelial cells, causing vasodilation due to nitric oxide release.

The binding of platelets to the endothelial cell receptor LOX-1 causes a release of endothelin, which induces endothelial dysfunction.[18]

Clinical significance

The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems.[1] Among numerous diseases potentially occurring from endothelin dysregulation are:

In insulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevates blood pressure.[22]

ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.[23]

In preliminary research, injection of endothelin-1 into a lateral cerebral ventricle was shown to potently stimulate glucose metabolism in specified interconnected circuits of the brain, and to induce convulsions, indicating its potential for diverse neural effects in conditions such as epilepsy.[24] Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions.[2]

Antagonists

Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788. An ETA-selective antagonist, ambrisentan was approved for treatment of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver.[1] Bosentan was a precursor to macitentan, which was approved in 2013.[1]

Notes and References

  1. Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, Pollock DM, Webb DJ, Maguire JJ . 6 . Endothelin . Pharmacological Reviews . 68 . 2 . 357–418 . April 2016 . 26956245 . 4815360 . 10.1124/pr.115.011833 .
  2. Kawanabe Y, Nauli SM . Endothelin . Cellular and Molecular Life Sciences . 68 . 2 . 195–203 . January 2011 . 20848158 . 3141212 . 10.1007/s00018-010-0518-0 .
  3. Kedzierski RM, Yanagisawa M . Endothelin system: the double-edged sword in health and disease . Annual Review of Pharmacology and Toxicology . 41 . 851–76 . 2001 . 11264479 . 10.1146/annurev.pharmtox.41.1.851 .
  4. Maguire JJ, Davenport AP . Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12 . British Journal of Pharmacology . 171 . 24 . 5555–72 . December 2014 . 25131455 . 4290702 . 10.1111/bph.12874 .
  5. Agapitov AV, Haynes WG . Role of endothelin in cardiovascular disease . Journal of the Renin-Angiotensin-Aldosterone System . 3 . 1 . 1–15 . March 2002 . 11984741 . 10.3317/jraas.2002.001 . 11382836 . free .
  6. Schinelli S . Pharmacology and physiopathology of the brain endothelin system: an overview . Current Medicinal Chemistry . 13 . 6 . 627–38 . 2006 . 16529555 . 10.2174/092986706776055652 .
  7. Kuang HY, Wu YH, Yi QJ, Tian J, Wu C, Shou WN, Lu TW . The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease: A systematic review and meta-analysis . Medicine . 97 . 10 . e0075 . March 2018 . 29517668 . 5882424 . 10.1097/MD.0000000000010075 .
  8. Iljazi A, Ayata C, Ashina M, Hougaard A . The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review . Current Pain and Headache Reports . 22 . 4 . 27 . March 2018 . 29557064 . 10.1007/s11916-018-0682-8 . 35440852 .
  9. Lu YP, Hasan AA, Zeng S, Hocher B . Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies . Kidney & Blood Pressure Research . 42 . 4 . 654–663 . 2017 . 29212079 . 10.1159/000482004 . free .
  10. Book: Ronald F. Tuma. Walter N. Durán. Klaus. Ley. vanc. Microcirculation. 2008. Elsevier/Academic Press. Amsterdam. 978-0-12-374530-9. 305–307. 2nd.
  11. Book: Walter F. . Boron. Emile L.. Boulpaep . vanc . Medical physiology a cellular and molecular approach. 2009. Saunders/Elsevier. Philadelphia, PA. 978-1-4377-2017-4. 480. 2nd International.
  12. Ling L, Maguire JJ, Davenport AP . Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer . British Journal of Pharmacology . 168 . 2 . 283–95 . January 2013 . 22118774 . 3572556 . 10.1111/j.1476-5381.2011.01786.x .
  13. Miyauchi T, Sakai S . Endothelin and the heart in health and diseases . Peptides . 111 . 77–88 . January 2019 . 30352269 . 10.1016/j.peptides.2018.10.002 . 53029198 .
  14. Book: Charles R. Craig. Robert E. Stitzel . vanc . Modern pharmacology with clinical applications. limited. 2004. Lippincott Williams & Wilkins. Philadelphia. 978-0-7817-3762-3. 215. 6th.
  15. Lange M, Pagotto U, Renner U, Arzberger T, Oeckler R, Stalla GK . The role of endothelins in the regulation of pituitary function . Experimental and Clinical Endocrinology & Diabetes . 110 . 3 . 103–12 . May 2002 . 12012269 . 10.1055/s-2002-29086 .
  16. Gross PM, Wainman DS, Espinosa FJ . Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1 . Endocrinology . 129 . 2 . 1110–2 . August 1991 . 1855455 . 10.1210/endo-129-2-1110 .
  17. Böhm F, Pernow J . 16753650 . The importance of endothelin-1 for vascular dysfunction in cardiovascular disease . Cardiovascular Research . 76 . 1 . 8–18 . October 2007 . 17617392 . 10.1016/j.cardiores.2007.06.004 . free .
  18. Kakutani M, Masaki T, Sawamura T . A platelet-endothelium interaction mediated by lectin-like oxidized low-density lipoprotein receptor-1 . Proceedings of the National Academy of Sciences of the United States of America . 97 . 1 . 360–4 . January 2000 . 10618423 . 26668 . 10.1016/j.biochi.2016.10.010 . 2000PNAS...97..360K .
  19. Bagnato A, Rosanò L . The endothelin axis in cancer . The International Journal of Biochemistry & Cell Biology . 40 . 8 . 1443–51 . 2008 . 18325824 . 10.1016/j.biocel.2008.01.022 .
  20. Macdonald RL, Pluta RM, Zhang JH . Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution . Nature Clinical Practice. Neurology . 3 . 5 . 256–63 . May 2007 . 17479073 . 10.1038/ncpneuro0490 . 19602552 .
  21. Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M . Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice . Neuroscience . 130 . 2 . 349–58 . 2005 . 15664691 . 10.1016/j.neuroscience.2004.09.036 . 23517779 .
  22. Potenza MA, Addabbo F, Montagnani M . Vascular actions of insulin with implications for endothelial dysfunction . American Journal of Physiology. Endocrinology and Metabolism . 297 . 3 . E568-77 . September 2009 . 19491294 . 10.1152/ajpendo.00297.2009 .
  23. Shemyakin A, Salehzadeh F, Böhm F, Al-Khalili L, Gonon A, Wagner H, Efendic S, Krook A, Pernow J . 6 . Regulation of glucose uptake by endothelin-1 in human skeletal muscle in vivo and in vitro . The Journal of Clinical Endocrinology and Metabolism . 95 . 5 . 2359–66 . May 2010 . 20207830 . 10.1210/jc.2009-1506 . free .
  24. Chew BH, Weaver DF, Gross PM . Dose-related potent brain stimulation by the neuropeptide endothelin-1 after intraventricular administration in conscious rats . Pharmacology, Biochemistry, and Behavior . 51 . 1 . 37–47 . May 1995 . 7617731 . 10.1016/0091-3057(94)00332-D . 9264919 .

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