Biology:Endothelin

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Endothelin family
1EDN human endothelin1 02.png
Identifiers
SymbolEndothelin
PfamPF00322
InterProIPR001928
PROSITEPDOC00243
SCOP21edp / SCOPe / SUPFAM
OPM superfamily147
OPM protein3cmh
Endothelin 1
Identifiers
SymbolEDN1
NCBI gene1906
HGNC3176
OMIM131240
RefSeqNM_001955
UniProtP05305
Other data
LocusChr. 6 p23-p24
Endothelin 2
Identifiers
SymbolEDN2
NCBI gene1907
HGNC3177
OMIM131241
RefSeqNM_001956
UniProtP20800
Other data
LocusChr. 1 p34
Endothelin 3
Identifiers
SymbolEDN3
HGNC3178
OMIM131242
RefSeqNM_000114
UniProtP14138
Other data
LocusChr. 20 q13.2-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.[17]

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.[10] 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]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 "Endothelin". Pharmacological Reviews 68 (2): 357–418. April 2016. doi:10.1124/pr.115.011833. PMID 26956245. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 "Endothelin". Cellular and Molecular Life Sciences 68 (2): 195–203. January 2011. doi:10.1007/s00018-010-0518-0. PMID 20848158. 
  3. ↑ "Endothelin system: the double-edged sword in health and disease". Annual Review of Pharmacology and Toxicology 41: 851–76. 2001. doi:10.1146/annurev.pharmtox.41.1.851. PMID 11264479. 
  4. ↑ "Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12". British Journal of Pharmacology 171 (24): 5555–72. December 2014. doi:10.1111/bph.12874. PMID 25131455. 
  5. ↑ "Role of endothelin in cardiovascular disease". Journal of the Renin-Angiotensin-Aldosterone System 3 (1): 1–15. March 2002. doi:10.3317/jraas.2002.001. PMID 11984741. 
  6. ↑ "Pharmacology and physiopathology of the brain endothelin system: an overview". Current Medicinal Chemistry 13 (6): 627–38. 2006. doi:10.2174/092986706776055652. PMID 16529555. 
  7. ↑ "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. doi:10.1097/MD.0000000000010075. PMID 29517668. 
  8. ↑ "The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review". Current Pain and Headache Reports 22 (4): 27. March 2018. doi:10.1007/s11916-018-0682-8. PMID 29557064. 
  9. ↑ "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. doi:10.1159/000482004. PMID 29212079. 
  10. ↑ 10.0 10.1 Tuma, Ronald F; Durán, Walter N; Ley, Klaus (2008). Microcirculation (2nd ed.). Amsterdam: Elsevier/Academic Press. pp. 305–307. ISBN 978-0-12-374530-9. https://archive.org/details/microcirculation0000unse/page/305. 
  11. ↑ Boron, Walter F.; Boulpaep, Emile L. (2009). Medical physiology a cellular and molecular approach (2nd International ed.). Philadelphia, PA: Saunders/Elsevier. pp. 480. ISBN 978-1-4377-2017-4. 
  12. ↑ 12.0 12.1 "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. doi:10.1111/j.1476-5381.2011.01786.x. PMID 22118774. 
  13. ↑ 13.0 13.1 13.2 13.3 "Endothelin and the heart in health and diseases". Peptides 111: 77–88. January 2019. doi:10.1016/j.peptides.2018.10.002. PMID 30352269. 
  14. ↑ Craig, Charles R; Stitzel, Robert E (2004). Modern pharmacology with clinical applications (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 215. ISBN 978-0-7817-3762-3. https://archive.org/details/modernpharmacolo00crcr. 
  15. ↑ "The role of endothelins in the regulation of pituitary function". Experimental and Clinical Endocrinology & Diabetes 110 (3): 103–12. May 2002. doi:10.1055/s-2002-29086. PMID 12012269. 
  16. ↑ "Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1". Endocrinology 129 (2): 1110–2. August 1991. doi:10.1210/endo-129-2-1110. PMID 1855455. 
  17. ↑ 17.0 17.1 "The importance of endothelin-1 for vascular dysfunction in cardiovascular disease". Cardiovascular Research 76 (1): 8–18. October 2007. doi:10.1016/j.cardiores.2007.06.004. PMID 17617392. 
  18. ↑ "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. doi:10.1016/j.biochi.2016.10.010. PMID 10618423. Bibcode: 2000PNAS...97..360K. 
  19. ↑ "The endothelin axis in cancer". The International Journal of Biochemistry & Cell Biology 40 (8): 1443–51. 2008. doi:10.1016/j.biocel.2008.01.022. PMID 18325824. 
  20. ↑ "Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution". Nature Clinical Practice. Neurology 3 (5): 256–63. May 2007. doi:10.1038/ncpneuro0490. PMID 17479073. 
  21. ↑ "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience 130 (2): 349–58. 2005. doi:10.1016/j.neuroscience.2004.09.036. PMID 15664691. 
  22. ↑ "Vascular actions of insulin with implications for endothelial dysfunction". American Journal of Physiology. Endocrinology and Metabolism 297 (3): E568-77. September 2009. doi:10.1152/ajpendo.00297.2009. PMID 19491294. 
  23. ↑ "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. doi:10.1210/jc.2009-1506. PMID 20207830. 
  24. ↑ "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. doi:10.1016/0091-3057(94)00332-D. PMID 7617731. 

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