Endothelin
Endothelins are peptides with receptors and effects in many body organs.  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.
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. As of 2018, endothelins remain under extensive basic and clinical research to define their roles in several organ systems.

# Etymology
Endothelins derived the name from their isolation in cultured endothelial cells.

# Isoforms
There are three isoforms of the peptide (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.

# Antagonists
Earliest antagonists discovered for ETA were BQ123, and for ETB, BQ788. 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of pulmonary arterial hypertension in 2007, followed by a more selective ETA antagonist, sitaxentan, which was later withdrawn due to potentially lethal effects in the liver. Bosentan was a precursor to macitentan, which was approved in 2013.

# Physiological effects
Endothelins are the most potent vasoconstrictors known. Overproduction of endothelin in the lungs may cause pulmonary hypertension, which was treatable in preliminary research by bosentan, sitaxentan or ambrisentan.
Endothelins have involvement in cardiovascular function, fluid-electrolyte homeostasis, and neuronal mechanisms across diverse cell types. Endothelin receptors are present in the three pituitary lobes which display increased metabolic activity when exposed to endothelin-1 in the blood or ventricular system.
ET-1 contributes to the vascular dysfunction associated with cardiovascular disease, particularly atherosclerosis and hypertension. 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.
The binding of platelets to the endothelial cell receptor LOX-1 causes a release of  endothelin, which induces endothelial dysfunction.

# Disease involvement
The ubiquitous distribution of endothelin peptides and receptors implicates involvement in a wide variety of physiological and pathological processes among different organ systems. Among numerous diseases potentially occurring from endothelin dysregulation are:
- several types of cancer
- cerebral vasospasm following subarachnoid hemorrhage
- arterial hypertension, pulmonary hypertension, and other cardiovascular disorders
- pain mediation
- cardiac hypertrophy and heart failure
- Dengue haemorrhagic fever
- Type II diabetes
- some cases of Hirschsprung disease
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.
ET-1 impairs glucose uptake in the skeletal muscles of insulin resistant subjects, thereby worsening insulin resistance.
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. Receptors for endothelin-1 exist in brain neurons, indicating a potential role in neural functions.

# Gene regulation
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.
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.
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 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.