Endothelin

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Endothelin family
SCOP2
1edp / SCOPe / SUPFAM
OPM superfamily147
OPM protein3cmh
Available protein structures:
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PDBsumstructure summary
Chr. 6 p23-p24
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DomainsInterPro
Chr. 1 p34
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Chr. 20 q13.2-q13.3
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Endothelins are peptides with

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

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

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]

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

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. ^
    PMID 26956245
    .
  2. ^
    PMID 20848158
    .
  3. PMID 11264479
    .
  4. PMID 25131455
    .
  5. S2CID 11382836
    .
  6. PMID 16529555
    .
  7. PMID 29517668
    .
  8. S2CID 35440852
    .
  9. PMID 29212079
    .
  10. ^
    ISBN 978-0-12-374530-9
    .
  11. ISBN 978-1-4377-2017-4
    .
  12. ^
    PMID 22118774
    .
  13. ^
    S2CID 53029198
    .
  14. ISBN 978-0-7817-3762-3
    .
  15. PMID 12012269
    .
  16. PMID 1855455
    .
  17. ^
    S2CID 16753650
    .
  18. PMID 10618423
    .
  19. PMID 18325824
    .
  20. S2CID 19602552
    .
  21. S2CID 23517779
    .
  22. PMID 19491294
    .
  23. PMID 20207830
    .
  24. S2CID 9264919
    .

External links
Retrieved from "https://en.wikipedia.org/w/index.php?title=Endothelin&oldid=1188960055"