Endothelin

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Endothelin-1
Endothelin-1
Sphere model according to PDB  1EDN

Existing structural data : 1edn , 1edp , 1t7h , 1v6r

Properties of human protein
Mass / length primary structure 21 amino acids
Identifier
Gene name EDN1
External IDs
Occurrence
Parent taxon Vertebrates

Endothelin-2
Properties of human protein
Mass / length primary structure 21 amino acids
Identifier
Gene name EDN2
External IDs

Endothelin-3
Properties of human protein
Mass / length primary structure 21 amino acids
Isoforms Long, short
Identifier
Gene name EDN3
External IDs

Endothelin e are peptide hormones in vertebrates that are mainly produced by the endothelium of blood vessels . Endothelins are the strongest known vasoconstrictor substances, but they also act in the central nervous system . Mutations in endothelin-3 encoding gene EDN3 rare to hereditary diseases Hirschsprung's disease , Ondine's curse and Waardenburg syndrome cause.

Paralogues

There are at least three known human paralogous variants of endothelin, all of which have the same number of 21 amino acids . Of these, endothelin-1 (ET-1) is characterized by a particularly potent effect in the cardiovascular system . In addition, the paralogues endothelin-2 (ET-2) and endothelin-3 (ET-3) are formed. While little is known about the function of endothelin-2, which is primarily formed in the kidneys, it has also been shown that endothelin-3 is important in the central nervous system (CNS). Two isoforms are known of ET-3 .

In addition, numerous structurally similar ingredients from snake venom are known (so-called sarafotoxins ) that have an endothelin effect .

function

As a blood vessel-changing (vasoactive) substance , it is a component of the body's own system for regulating blood pressure and a highly effective vasoconstrictor . Its vasoconstricting and thus blood pressure increasing effect is 100 times higher than that of noradrenaline . It was initially assumed that it was only formed in the endothelium , a layer of cells lining the inner wall of blood vessels throughout the body. In fact, however, many cells are able to produce and release endothelin.

Increased endothelin levels are often observed, especially in diseases of the coronary arteries , heart failure and arteriosclerosis . It also affects the contractility of the heart , the heart rhythm and the blood flow to the kidneys . The importance of endothelin in various types of cancer, especially prostate and breast cancer , has also been discussed for some time .

Receptors

Endothelin mediates its effects via G-protein-coupled receptors , the endothelin receptors . Currently, two receptor subtypes of the endothelin are known as ET A and ET B are designated. ET A receptors can be found in smooth muscle cells of the blood vessels, where they are responsible for the vasoconstriction caused by endothelin-1. ET B receptors, on the other hand, are detectable on endothelium, epithelial cells (ET-B1) and smooth muscle cells (ET-B2). Activation of endothelial ET B receptors by endothelin-1 or endothelin-3 can result in both vasodilation (ET-B1: via the release of nitric oxide (NO)) and vasoconstriction (ET-B2).

Endothelin receptor antagonists

The effect of endothelin can be inhibited with the help of so-called endothelin receptor antagonists , in the simplest case by blocking the endothelin receptors. These antagonists (e.g. ambrisentan , atrasentan , bosentan , clazosentan , macitentan , sitaxentan and tezosentan ) are currently used in particular as orphan drugs in the treatment of pulmonary arterial hypertension . Endothelin receptor antagonists are also approved for the treatment of digital ulcerations in connection with systemic sclerosis . Clinical studies also provide evidence of efficacy in treating cerebral vasospasm in subarachnoid hemorrhage , although the overall therapeutic benefit is unclear. A possible use of endothelin receptor antagonists for other areas of application, such as chronic kidney failure , arterial hypertension , heart failure and various forms of cancer, was examined in clinical studies with no satisfactory result.

literature

Individual evidence

  1. ↑ Orthologist at eggNOG
  2. ↑ endothelin.  In: Online Mendelian Inheritance in Man . (English)
  3. ↑ UniProt P05305 , UniProt P20800 , UniProt P14138
  4. ↑ J. Guo, Z. Shi, K. Yang, JH Tian, ​​L. Jiang: Endothelin receptor antagonists for subarachnoid hemorrhage . In: Cochrane Database Syst Rev . 9, 2012, pp. CD008354-CD008354. ISSN  1469-493X . doi : 10.1002 / 14651858.CD008354.pub2 . PMID 22972119 .
  5. ↑ DE Kohan, JG Cleland, LJ Rubin, D. Theodorescu, M. Barton: Clinical trials with endothelin receptor antagonists: what went wrong and where can we improve? . In: Life Sci . 91, No. 13-14, October 2012, pp. 528-539. ISSN  1879-0631 . doi : 10.1016 / j.lfs.2012.07.034 . PMID 22967485 .