World Library  
Flag as Inappropriate
Email this Article


Article Id: WHEBN0002578537
Reproduction Date:

Title: Endothelin  
Author: World Heritage Encyclopedia
Language: English
Subject: Vasoconstriction, Intracranial aneurysm, Vasodilation, Pathophysiology of hypertension, Endothelin receptor antagonists
Collection: Hormones of the Blood Vessels, Peptide Hormones
Publisher: World Heritage Encyclopedia


Endothelin family
Symbol Endothelin
Pfam PF00322
InterPro IPR001928
SCOP 1edp
OPM superfamily 156
OPM protein 3cmh
Endothelin 1
Symbol EDN1
Entrez 1906
HUGO 3176
OMIM 131240
RefSeq NM_001955
UniProt P05305
Other data
Locus Chr. 6 p23-p24
Endothelin 2
Symbol EDN2
Entrez 1907
HUGO 3177
OMIM 131241
RefSeq NM_001956
UniProt P20800
Other data
Locus Chr. 1 p34
Endothelin 3
Symbol EDN3
HUGO 3178
OMIM 131242
RefSeq NM_000114
UniProt P14138
Other data
Locus Chr. 20 q13.2-q13.3

Endothelins are peptides that constrict blood vessels and raise blood pressure. They are normally kept in balance by other mechanisms, but when they are over-expressed, they contribute to high blood pressure (hypertension) and heart disease.

Endothelins are 21-

  • Historical background and discovery of endothelin
  • The International Conferences on Endothelin (Est. 1988)
  • Endothelin science (Actelion Pharmaceuticals)
  • Endothelins at the US National Library of Medicine Medical Subject Headings (MeSH)

External links

  • Kedzierski RM, Yanagisawa M; Yanagisawa (2001). "Endothelin system: the double-edged sword in health and disease". Annu. Rev. Pharmacol. Toxicol. 41: 851–76.  
  • Barton M, Yanagisawa M; Yanagisawa (2008). "Endothelin: 20 years from discovery to therapy". Can. J. Physiol. Pharmacol. 86 (8): 485–98.  

Further reading

  1. ^ Agapitov AV, Haynes WG; Haynes (March 2002). "Role of endothelin in cardiovascular disease". J Renin Angiotensin Aldosterone Syst 3 (1): 1–15.  
  2. ^ Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Curr. Med. Chem. 13 (6): 627–38.  
  3. ^ a b Microcirculation (2nd ed.). Amsterdam: Elsevier/Academic Press. 2008. pp. 305–307.  
  4. ^ Medical physiology a cellular and molecular approach (2nd ed., International ed.). Philadelphia, PA: Saunders/Elsevier. 2009. p. 480.  
  5. ^ Modern pharmacology with clinical applications (6th ed.). Philadelphia: Lippincott Williams & Wilkins. 2004. p. 215.  
  6. ^ Bagnato A, Rosanò L; Rosanò (2008). "The endothelin axis in cancer". Int. J. Biochem. Cell Biol. 40 (8): 1443–51.  
  7. ^ Macdonald RL, Pluta RM, Zhang JH; Pluta; Zhang (May 2007). "Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution". Nat Clin Pract Neurol 3 (5): 256–63.  
  8. ^ Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M; Kuwaki; Kisanuki; Yanagisawa; Moriya; Fukuda; Shimoyama (2005). "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience 130 (2): 349–58.  
  9. ^ Mawji IA, Robb GB, Tai SC, Marsden PA; Robb; Tai; Marsden (March 2004). "Role of the 3'-untranslated region of human endothelin-1 in vascular endothelial cells. Contribution to transcript lability and the cellular heat shock response". J. Biol. Chem. 279 (10): 8655–67.  


The ET-1 transcript is constitutively destabilized by its 3'-UTR through two destabilizing elements, DE1 and DE2. DE1 functions through a conserved ARE by the AUF1-proteasome pathway and is regulated by the heat shock pathway.[9]

Recent studies have revealed a functional link between AUF1, heat shock proteins and the ubiquitin-proteasome network. Proteasome inhibition by chemical inhibition or heat shock was shown to stabilize a model ARE-containing mRNA whereas promotion of cellular ubiquitination pathways was shown to accelerate ARE mRNA turnover. Studies with in vitro proteasome preparations suggest that the proteasome itself may possess ARE-specific RNA destabilizing activity. The ARE-binding protein AUF1 has been linked to the ubiquitin-proteasome pathway. AUF1 mRNA destabilizing activity has been positively correlated with its level of polyubiquitination and has been shown to interact with a member of the E2 ubiquitin-conjugating protein family. Furthermore, under conditions of cellular heat shock AUF1 associates with heat shock protein 70 (HSP70), which itself possesses ARE binding activity.

The ET-1 mRNA is labile with a half-life of less than an hour. Together, the combined actions of ET-1 transcription and rapid mRNA turnover allow for stringent control over its expression. It has previously been shown that ET-1 mRNA is selectively stabilized in response to cellular activation by Escherichia coli O157:H7-derived verotoxins, suggesting ET-1 is regulated by post-transcriptional mechanisms. Regulatory elements modulating mRNA half-life are often found within 3'-untranslated regions (3'-UTR). The 1.1-kb 3'-UTR of human ET-1 accounts for over 50% of the transcript length and features long tracts of highly conserved sequences including an AU-rich region. Some 3'-UTR AU-rich elements (AREs) play important regulatory roles in cytokine and proto-oncogene expression by influencing half-life under basal conditions and in response to cellular activation. Several RNA-binding proteins with affinities for AREs have been characterized including AUF1 (hnRNPD), the ELAV family (HuR, HuB, HuC, HuD), tristetraprolin, TIA/TIAR, HSP70, and others. Although specific mechanisms directing ARE activity have not been fully elucidated, current models suggest ARE-binding proteins target specific mRNAs to cellular pathways that influence 3'-polyadenylate tail and 5'-cap metabolism.

The endothelium regulates local vascular tone and integrity through the coordinated release of vasoactive molecules. Secretion of endothelin-1 (ET-1)1 from the endothelium signals vasoconstriction and influences local cellular growth and survival. ET-1 has been implicated in the development and progression of vascular disorders such as atherosclerosis and hypertension. Endothelial cells upregulate ET-1 in response to hypoxia, oxidized LDL, pro-inflammatory cytokines, and bacterial toxins. Initial studies on the ET-1 promoter provided some of the earliest mechanistic insight into endothelial-specific gene regulation. Numerous studies have since provided valuable insight into ET-1 promoter regulation under basal and activated cellular states.

Gene regulation

The ubiquitous distribution of endothelin peptides and receptors implicates its involvement in a wide variety of physiological and pathological processes in the body. Among numerous diseases potentially occurring from endothelin dysregulation are

Disease involvement

Overproduction of endothelin in the lungs may cause pulmonary hypertension, which can sometimes be treated by the use of an endothelin receptor antagonist, such as bosentan, sitaxentan or ambrisentan. The latter drug selectively blocks endothelin A receptors, decreasing the vasoconstrictive actions and allowing for increased beneficial effects of endothelin B stimulation, such as nitric oxide production. The precise effects of endothelin B receptor activation depends on the type of cells involved.

Endothelins are the most potent vasoconstrictors known.[5] In a healthy individual, a delicate balance between vasoconstriction and vasodilation is maintained by endothelin and other vasoconstrictors on the one hand and nitric oxide, prostacyclin and other vasodilators on the other.

Examples of physiological interaction

Earliest antagonists discovered for ETA is BQ123, and that for ETB is BQ788.[3]


There are three isoforms (identified as ET-1, -2, -3) with varying regions of expression and binding to at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC.[4]


Endothelins derived the name from the fact that they were derived and secreted from cultured endothelial cells.[3]



  • Etymology 1
  • Isoforms 2
  • Antagonists 3
  • Examples of physiological interaction 4
  • Disease involvement 5
  • Gene regulation 6
  • References 7
  • Further reading 8
  • External links 9


This article was sourced from Creative Commons Attribution-ShareAlike License; additional terms may apply. World Heritage Encyclopedia content is assembled from numerous content providers, Open Access Publishing, and in compliance with The Fair Access to Science and Technology Research Act (FASTR), Wikimedia Foundation, Inc., Public Library of Science, The Encyclopedia of Life, Open Book Publishers (OBP), PubMed, U.S. National Library of Medicine, National Center for Biotechnology Information, U.S. National Library of Medicine, National Institutes of Health (NIH), U.S. Department of Health & Human Services, and, which sources content from all federal, state, local, tribal, and territorial government publication portals (.gov, .mil, .edu). Funding for and content contributors is made possible from the U.S. Congress, E-Government Act of 2002.
Crowd sourced content that is contributed to World Heritage Encyclopedia is peer reviewed and edited by our editorial staff to ensure quality scholarly research articles.
By using this site, you agree to the Terms of Use and Privacy Policy. World Heritage Encyclopedia™ is a registered trademark of the World Public Library Association, a non-profit organization.

Copyright © World Library Foundation. All rights reserved. eBooks from Project Gutenberg are sponsored by the World Library Foundation,
a 501c(4) Member's Support Non-Profit Organization, and is NOT affiliated with any governmental agency or department.