| Endothelin family | |||||||||
|---|---|---|---|---|---|---|---|---|---|
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| Identifiers | |||||||||
| Symbol | Endothelin | ||||||||
| Pfam | PF00322 | ||||||||
| InterPro | IPR001928 | ||||||||
| PROSITE | PDOC00243 | ||||||||
| SCOP2 | 1edp /SCOPe /SUPFAM | ||||||||
| OPM superfamily | 147 | ||||||||
| OPM protein | 3cmh | ||||||||
| |||||||||
| Endothelin 1 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | EDN1 | ||||||
| NCBI gene | 1906 | ||||||
| HGNC | 3176 | ||||||
| OMIM | 131240 | ||||||
| RefSeq | NM_001955 | ||||||
| UniProt | P05305 | ||||||
| Other data | |||||||
| Locus | Chr. 6p23-p24 | ||||||
| |||||||
| Endothelin 2 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | EDN2 | ||||||
| NCBI gene | 1907 | ||||||
| HGNC | 3177 | ||||||
| OMIM | 131241 | ||||||
| RefSeq | NM_001956 | ||||||
| UniProt | P20800 | ||||||
| Other data | |||||||
| Locus | Chr. 1p34 | ||||||
| |||||||
| Endothelin 3 | |||||||
|---|---|---|---|---|---|---|---|
| Identifiers | |||||||
| Symbol | EDN3 | ||||||
| HGNC | 3178 | ||||||
| OMIM | 131242 | ||||||
| RefSeq | NM_000114 | ||||||
| UniProt | P14138 | ||||||
| Other data | |||||||
| Locus | Chr. 20q13.2-q13.3 | ||||||
| |||||||
Endothelins are peptides withreceptors 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 whenoverexpressed, they contribute to high blood pressure (hypertension),heart disease, and potentially other diseases.[1][4]
Endothelins are 21-amino acidvasoconstrictingpeptides produced primarily in theendothelium having a key role invascular 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 extensivebasic andclinical research to define their roles in several organ systems.[1][7][8][9]
Endothelins derived the name from their isolation in culturedendothelial cells.[1][10]
There are threeisoforms 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 knownendothelin receptors, ETA, ETB1, ETB2 and ETC.[1][11]
The humangenes for endothelin-1 (ET-1),endothelin-2 (ET-2), and endothelin-3 (ET-3) are located onchromosomes 6, 1, and 20, respectively.[2]
Endothelin functions through activation of twoG 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 andorgans, 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 powerfulendogenous chemical affecting vascular tone across organ systems.[2][13] Secretion of endothelin-1 from the vascularendothelium signals vasoconstriction and influences local cellular growth and survival.[13] ET-1 has been implicated in the development and progression of severalcardiovascular diseases, such asatherosclerosis andhypertension.[13] Endothelin also has roles inmitogenesis, cell survival,angiogenesis, bone growth,nociceptor function, and cancer onset mechanisms.[2] Clinically,anti-ET drugs are used to treatpulmonary 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]
Endothelins are the most potent vasoconstrictors known.[1][14] Overproduction of endothelin in the lungs may causepulmonary hypertension, which was treatable in preliminary research bybosentan,sitaxentan orambrisentan.[1]
Endothelins have involvement in cardiovascular function, fluid-electrolytehomeostasis, and neuronal mechanisms across diverse cell types.[1] Endothelin receptors are present in the threepituitary 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, particularlyatherosclerosis andhypertension.[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 tonitric oxide release.[17]
The binding ofplatelets to theendothelial cell receptorLOX-1 causes a release of endothelin, which inducesendothelial dysfunction.[18]
The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among differentorgan systems.[1] Among numerous diseases potentially occurring from endothelin dysregulation are:
Ininsulin resistance the high levels of blood insulin results in increased production and activity of ET-1, which promotes vasoconstriction and elevatesblood pressure.[22]
ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worseninginsulin resistance.[23]
In preliminary research, injection of endothelin-1 into alateral cerebral ventricle was shown to potently stimulateglucose metabolism in specified interconnected circuits of the brain, and to induceconvulsions, indicating its potential for diverse neural effects in conditions such asepilepsy.[24] Receptors for endothelin-1 exist in brainneurons, indicating a potential role in neural functions.[2]
Earliest antagonists discovered for ETA wereBQ123, and for ETB,BQ788.[10] An ETA-selective antagonist,ambrisentan was approved for treatment ofpulmonary 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 tomacitentan, which was approved in 2013.[1]
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