Endothelin

Last updated
Endothelin family
1EDN human endothelin1 02.png
Identifiers
SymbolEndothelin
Pfam PF00322
InterPro IPR001928
PROSITE PDOC00243
SCOP2 1edp / SCOPe / SUPFAM
OPM superfamily 147
OPM protein 3cmh
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
Endothelin 1
Identifiers
Symbol EDN1
NCBI gene 1906
HGNC 3176
OMIM 131240
RefSeq NM_001955
UniProt P05305
Other data
Locus Chr. 6 p23-p24
Search for
Structures Swiss-model
Domains InterPro
Endothelin 2
Identifiers
Symbol EDN2
NCBI gene 1907
HGNC 3177
OMIM 131241
RefSeq NM_001956
UniProt P20800
Other data
Locus Chr. 1 p34
Search for
Structures Swiss-model
Domains InterPro
Endothelin 3
Identifiers
Symbol EDN3
HGNC 3178
OMIM 131242
RefSeq NM_000114
UniProt P14138
Other data
Locus Chr. 20 q13.2-q13.3
Search for
Structures Swiss-model
Domains InterPro

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]

Contents

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]

Related Research Articles

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The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid and electrolyte balance, and systemic vascular resistance.

<span class="mw-page-title-main">Endothelium</span> Layer of cells that lining inner surface of blood vessels

The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. Endothelial cells form the barrier between vessels and tissue and control the flow of substances and fluid into and out of a tissue.

<span class="mw-page-title-main">Pulmonary hypertension</span> Increased blood pressure in lung arteries

Pulmonary hypertension is a condition of increased blood pressure in the arteries of the lungs. Symptoms include shortness of breath, fainting, tiredness, chest pain, swelling of the legs, and a fast heartbeat. The condition may make it difficult to exercise. Onset is typically gradual. According to the definition at the 6th World Symposium of Pulmonary Hypertension in 2018, a patient is deemed to have pulmonary hypertension if the pulmonary mean arterial pressure is greater than 20mmHg at rest, revised down from a purely arbitrary 25mmHg, and pulmonary vascular resistance (PVR) greater than 3 Wood units.

The angiotensin II receptors, (ATR1) and (ATR2), are a class of G protein-coupled receptors with angiotensin II as their ligands. They are important in the renin–angiotensin system: they are responsible for the signal transduction of the vasoconstricting stimulus of the main effector hormone, angiotensin II.

<span class="mw-page-title-main">Sitaxentan</span> Chemical compound

Sitaxentan sodium (TBC-11251) is a medication for the treatment of pulmonary arterial hypertension (PAH). It was marketed as Thelin by Encysive Pharmaceuticals until Pfizer purchased Encysive in February 2008. In 2010, Pfizer voluntarily removed sitaxentan from the market due to concerns about liver toxicity.

An endothelin receptor antagonist (ERA) is a drug that blocks endothelin receptors.

<span class="mw-page-title-main">Bosentan</span> Medication

Bosentan, sold under the brand name Tracleer among others, is a dual endothelin receptor antagonist medication used in the treatment of pulmonary artery hypertension (PAH).

The epoxyeicosatrienoic acids or EETs are signaling molecules formed within various types of cells by the metabolism of arachidonic acid by a specific subset of Cytochrome P450 enzymes termed cytochrome P450 epoxygenases. These nonclassic eicosanoids are generally short-lived, being rapidly converted from epoxides to less active or inactive dihydroxy-eicosatrienoic acids (diHETrEs) by a widely distributed cellular enzyme, Soluble epoxide hydrolase (sEH), also termed Epoxide hydrolase 2. The EETs consequently function as transiently acting, short-range hormones; that is, they work locally to regulate the function of the cells that produce them or of nearby cells. The EETs have been most studied in animal models where they show the ability to lower blood pressure possibly by a) stimulating arterial vasorelaxation and b) inhibiting the kidney's retention of salts and water to decrease intravascular blood volume. In these models, EETs prevent arterial occlusive diseases such as heart attacks and brain strokes not only by their anti-hypertension action but possibly also by their anti-inflammatory effects on blood vessels, their inhibition of platelet activation and thereby blood clotting, and/or their promotion of pro-fibrinolytic removal of blood clots. With respect to their effects on the heart, the EETs are often termed cardio-protective. Beyond these cardiovascular actions that may prevent various cardiovascular diseases, studies have implicated the EETs in the pathological growth of certain types of cancer and in the physiological and possibly pathological perception of neuropathic pain. While studies to date imply that the EETs, EET-forming epoxygenases, and EET-inactivating sEH can be manipulated to control a wide range of human diseases, clinical studies have yet to prove this. Determination of the role of the EETS in human diseases is made particularly difficult because of the large number of EET-forming epoxygenases, large number of epoxygenase substrates other than arachidonic acid, and the large number of activities, some of which may be pathological or injurious, that the EETs possess.

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There are at least four known endothelin receptors, ETA, ETB1, ETB2 and ETC, all of which are G protein-coupled receptors whose activation result in elevation of intracellular-free calcium, which constricts the smooth muscles of the blood vessels, raising blood pressure, or relaxes the smooth muscles of the blood vessels, lowering blood pressure, among other functions.

<span class="mw-page-title-main">Natriuretic peptide</span>

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<span class="mw-page-title-main">Glucagon-like peptide-1 receptor</span> Receptor activated by peptide hormone GLP-1

The glucagon-like peptide-1 receptor (GLP1R) is a G protein-coupled receptor (GPCR) found on beta cells of the pancreas and on neurons of the brain. It is involved in the control of blood sugar level by enhancing insulin secretion. In humans it is synthesised by the gene GLP1R, which is present on chromosome 6. It is a member of the glucagon receptor family of GPCRs. GLP1R is composed of two domains, one extracellular (ECD) that binds the C-terminal helix of GLP-1, and one transmembrane (TMD) domain that binds the N-terminal region of GLP-1. In the TMD domain there is a fulcrum of polar residues that regulates the biased signaling of the receptor while the transmembrane helical boundaries and extracellular surface are a trigger for biased agonism.

<span class="mw-page-title-main">Ambrisentan</span> Chemical compound

Ambrisentan is a drug indicated for use in the treatment of pulmonary hypertension.

<span class="mw-page-title-main">Endothelin 1</span>

Endothelin 1 (ET-1), also known as preproendothelin-1 (PPET1), is a potent vasoconstrictor peptide produced by vascular endothelial cells. The protein encoded by this gene – EDN1 – is proteolytically processed to release endothelin 1. Endothelin 1 is one of three isoforms of human endothelin.

<span class="mw-page-title-main">Endothelin receptor type B</span> Protein-coding gene in the species Homo sapiens

Endothelin receptor type B, (ET-B) is a protein that in humans is encoded by the EDNRB gene.

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<span class="mw-page-title-main">Pathophysiology of hypertension</span>

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<span class="mw-page-title-main">Endothelin 2</span> Protein-coding gene in the species Homo sapiens

Endothelin 2 (ET-2) is a protein encoded by the EDN2 gene in humans. It was first discovered in 1988 by Yanagisawa and team and belongs to a family of three endothelin peptide isoforms, which constrict blood vessels. ET-2 is encoded by genes on separate chromosomes to its isoforms and is mainly produced in vascular endothelial cells of the kidney, placenta, uterus, heart, central nervous system and intestine. It becomes present in the blood of animals and humans at levels ranging from 0.3pg/ml to 3pg/ml. ET-2 acts by binding to two different G-protein coupled receptors (GPCRs), the endothelin A receptor (EDNRA) and the endothelin B receptor (EDNRB).

<span class="mw-page-title-main">Macitentan</span> Chemical compound

Macitentan, sold under the brand name Opsumit, is an endothelin receptor antagonist (ERA) developed by Actelion and approved for the treatment of pulmonary arterial hypertension (PAH). The other two ERAs marketed as of 2014 are bosentan and ambrisentan. Macitentan is a dual ERA, meaning that it acts as an antagonist of two endothelin (ET) receptor subtypes, ETA and ETB. However, macitentan has a 50-fold increased selectivity for the ETA subtype compared to the ETB subtype. The drug received approval from the U.S. Food and Drug Administration (FDA) on October 13, 2013.

<span class="mw-page-title-main">Sarafotoxin</span>

Sarafotoxins (SRTXs) are a group of toxins present in the venom of Atractaspis engaddensis, and in clinical trials cause similar symptoms to patients diagnosed with acute giardiasis. Their etymology is from the name of the snake "שרף עין גדי" in Hebrew, pronounced "Saraf Ein Gedi". Together with endothelins (ETs), they form a homogenous family of strong vasoconstrictor isopeptides. Among them, a few slightly different substances can be named as SRTX-a, SRTX-b, SRTX-c, which were initially derived from A. engaddensis. Each one contains twenty-one amino acid residues that spontaneously fold into a defined tertiary structure, with two interchain-cysteine linkages and a long hydrophobic tail. There are also other compounds, however, they are mostly derivations of previously mentioned ones. The main differences in the family of endothelin and sarafotoxins appear at N-terminal of peptides, as C-terminal in all of them is almost the same.

References

  1. 1 2 3 4 5 6 7 8 9 10 11 Davenport AP, Hyndman KA, Dhaun N, Southan C, Kohan DE, Pollock JS, et al. (April 2016). "Endothelin". Pharmacological Reviews. 68 (2): 357–418. doi:10.1124/pr.115.011833. PMC   4815360 . PMID   26956245.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 Kawanabe Y, Nauli SM (January 2011). "Endothelin". Cellular and Molecular Life Sciences. 68 (2): 195–203. doi:10.1007/s00018-010-0518-0. PMC   3141212 . PMID   20848158.
  3. ↑ Kedzierski RM, Yanagisawa M (2001). "Endothelin system: the double-edged sword in health and disease". Annual Review of Pharmacology and Toxicology. 41: 851–76. doi:10.1146/annurev.pharmtox.41.1.851. PMID   11264479.
  4. ↑ Maguire JJ, Davenport AP (December 2014). "Endothelin@25 - new agonists, antagonists, inhibitors and emerging research frontiers: IUPHAR Review 12". British Journal of Pharmacology. 171 (24): 5555–72. doi:10.1111/bph.12874. PMC   4290702 . PMID   25131455.
  5. ↑ Agapitov AV, Haynes WG (March 2002). "Role of endothelin in cardiovascular disease". Journal of the Renin-Angiotensin-Aldosterone System. 3 (1): 1–15. doi: 10.3317/jraas.2002.001 . PMID   11984741. S2CID   11382836.
  6. ↑ Schinelli S (2006). "Pharmacology and physiopathology of the brain endothelin system: an overview". Current Medicinal Chemistry. 13 (6): 627–38. doi:10.2174/092986706776055652. PMID   16529555.
  7. ↑ Kuang HY, Wu YH, Yi QJ, Tian J, Wu C, Shou WN, Lu TW (March 2018). "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. doi:10.1097/MD.0000000000010075. PMC   5882424 . PMID   29517668.
  8. ↑ Iljazi A, Ayata C, Ashina M, Hougaard A (March 2018). "The Role of Endothelin in the Pathophysiology of Migraine-a Systematic Review". Current Pain and Headache Reports. 22 (4): 27. doi:10.1007/s11916-018-0682-8. PMID   29557064. S2CID   35440852.
  9. ↑ Lu YP, Hasan AA, Zeng S, Hocher B (2017). "Plasma ET-1 Concentrations Are Elevated in Pregnant Women with Hypertension -Meta-Analysis of Clinical Studies". Kidney & Blood Pressure Research. 42 (4): 654–663. doi: 10.1159/000482004 . PMID   29212079.
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  11. ↑ Boron WF, Boulpaep EL (2009). Medical physiology a cellular and molecular approach (2nd International ed.). Philadelphia, PA: Saunders/Elsevier. p. 480. ISBN   978-1-4377-2017-4.
  12. 1 2 Ling L, Maguire JJ, Davenport AP (January 2013). "Endothelin-2, the forgotten isoform: emerging role in the cardiovascular system, ovarian development, immunology and cancer". British Journal of Pharmacology. 168 (2): 283–95. doi:10.1111/j.1476-5381.2011.01786.x. PMC   3572556 . PMID   22118774.
  13. 1 2 3 4 Miyauchi T, Sakai S (January 2019). "Endothelin and the heart in health and diseases". Peptides. 111: 77–88. doi:10.1016/j.peptides.2018.10.002. PMID   30352269. S2CID   53029198.
  14. ↑ Craig CR, Stitzel RE (2004). Modern pharmacology with clinical applications (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp.  215. ISBN   978-0-7817-3762-3.
  15. ↑ Lange M, Pagotto U, Renner U, Arzberger T, Oeckler R, Stalla GK (May 2002). "The role of endothelins in the regulation of pituitary function". Experimental and Clinical Endocrinology & Diabetes. 110 (3): 103–12. doi:10.1055/s-2002-29086. PMID   12012269.
  16. ↑ Gross PM, Wainman DS, Espinosa FJ (August 1991). "Differentiated metabolic stimulation of rat pituitary lobes by peripheral and central endothelin-1". Endocrinology. 129 (2): 1110–2. doi:10.1210/endo-129-2-1110. PMID   1855455.
  17. 1 2 Böhm F, Pernow J (October 2007). "The importance of endothelin-1 for vascular dysfunction in cardiovascular disease". Cardiovascular Research. 76 (1): 8–18. doi: 10.1016/j.cardiores.2007.06.004 . PMID   17617392. S2CID   16753650.
  18. ↑ Kakutani M, Masaki T, Sawamura T (January 2000). "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. Bibcode:2000PNAS...97..360K. doi:10.1016/j.biochi.2016.10.010. PMC   26668 . PMID   10618423.
  19. ↑ Bagnato A, Rosanò L (2008). "The endothelin axis in cancer". The International Journal of Biochemistry & Cell Biology. 40 (8): 1443–51. doi:10.1016/j.biocel.2008.01.022. PMID   18325824.
  20. ↑ Macdonald RL, Pluta RM, Zhang JH (May 2007). "Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution". Nature Clinical Practice. Neurology. 3 (5): 256–63. doi:10.1038/ncpneuro0490. PMID   17479073. S2CID   19602552.
  21. ↑ Hasue F, Kuwaki T, Kisanuki YY, Yanagisawa M, Moriya H, Fukuda Y, Shimoyama M (2005). "Increased sensitivity to acute and persistent pain in neuron-specific endothelin-1 knockout mice". Neuroscience. 130 (2): 349–58. doi:10.1016/j.neuroscience.2004.09.036. PMID   15664691. S2CID   23517779.
  22. ↑ Potenza MA, Addabbo F, Montagnani M (September 2009). "Vascular actions of insulin with implications for endothelial dysfunction". American Journal of Physiology. Endocrinology and Metabolism. 297 (3): E568-77. doi:10.1152/ajpendo.00297.2009. PMID   19491294.
  23. ↑ Shemyakin A, Salehzadeh F, Böhm F, Al-Khalili L, Gonon A, Wagner H, et al. (May 2010). "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. doi: 10.1210/jc.2009-1506 . PMID   20207830.
  24. ↑ Chew BH, Weaver DF, Gross PM (May 1995). "Dose-related potent brain stimulation by the neuropeptide endothelin-1 after intraventricular administration in conscious rats". Pharmacology, Biochemistry, and Behavior. 51 (1): 37–47. doi:10.1016/0091-3057(94)00332-D. PMID   7617731. S2CID   9264919.
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