Endothelins and Related Peptides

What is endothelin?

Isolated and discovered first from cultivated swine endothelial cells' conditioned media in 1987, endothelin (ET) is a powerful vasoconstrictive peptide with 21 amino acid residues. Because of its persistent pressor response after infusion into rats and its powerful, long-lasting constriction of isolated vascular beds, ET sparked interest globally upon its discovery. Two more genes producing ET-like peptides were identified shortly after ET was discovered by research of the ET gene. These peptides had an extremely similar sequence of amino acids with the first ET ever observed. This led to the designation of ET-1, ET-2, and ET-3 for the three endogenous isoforms. There are three distinct peptides, each with 21 amino acid residues, and their expression varies across different cell types and organs. Among endothelial cells, ET-1 is the most abundant. The asp's cardiotoxic venom contains a surprising cluster of related peptides called sarafotoxins (SRTXs). So far, four different variants of SRTX have been detected: SRTX-a, SRTX-b, SRTX-c (S6c), and SRTX-e. The fact that snakes utilize these identical peptides as an exocrine poison and mammals as an endocrine signal is fascinating, given that they likely developed from the same ancestor.

Endothelin 1

A 21-amino-acid peptide with two cysteine bridges at the N terminus and a hydrophobic C terminus, ET-1 is the principal member of the endothelin peptide family. Additionally, endothelins consist of ET-3 and vasoactive intestinal contractor, which is the mouse version of ET-2. Because endothelins and snake venom toxins are structurally similar, antivenoms based on orally active endothelin receptor antagonists (ERAs) have been considered. Almost all cell types produce mature ET-1 peptide, however it is highly expressed in cells of the following types: smooth muscle cells and vascular endothelial cells; cells of the airway epithelium and smooth muscle cells; macrophages; fibroblasts; cells of the heart muscle, mesangial cells, podocytes, and neurons in the brain. It took almost twenty-five years of data collection, but McPherson and Larson finally cracked the ET-1 peptide's crystal structure. ET-2 has a role in ovulation, thermoregulation, intestinal contraction, lung alveolarization, and is expressed in intestinal and ovarian epithelial cells. There is a critical and largely unrecognized function of ET-2 in physiology and illness; mice defective in ET-2 die at a young age, and its deletion causes hypothermia, emphysema, growth retardation, and metabolic abnormalities (such as hypoglycemia and ketoanemia). ET-3 is expressed in various cell types, including the placenta, brain neurons, intestinal epithelial cells, renal tubular epithelial cells, and others. Its main function is to facilitate the release of vasodilator and anti-inflammatory molecules, like prostacyclin and NO, and it may even stimulate the growth of specific cell types, like melanocytes.

Endothelin 2

Although there is a relatively substantial Leu-to-Trp change at position 6, the binding affinity is little affected by the two amino acid difference between ET-1 and ET-2. The peptide ET-2 has not been investigated as much as ET-1, despite the fact that it is just as effective as ET-1 as a vasoconstrictor. It has been discovered that the human circulatory system contains ET-2 peptide and ET-2 messenger RNA (mRNA). The presence of ET-2 mRNA and its precursor, Big ET-2, in the cytoplasm of endothelial cells raises the possibility that this peptide is released locally from endothelial cells and helps to maintain tone. The fact that Big ET-2 is more abundant than Big ET-1 in healthy human plasma lends credence to this theory. A specialized enzyme-linked immunosorbent test (ELISA) that does not react with ET-1 may be used to measure ET-2 levels in plasma, with an average value of 0.9±0.03 pmol/l in 40 participants. Human failing hearts have also been shown to contain ET-2. Nevertheless, the exact function of this isoform in normal or diseased physiological processes is yet unknown.

Endothelin 3

Although endothelial cells are unable to produce ET-3, both the mature peptide and Big ET-3 may be found in plasma and several other organs, such as the brain and heart. Big ET-3 could perhaps originate in the adrenal gland as well. Secretory cells of the medulla were marked by antisera to this precursor; however, mature ET-3 was not found in adrenal tissue homogenates. The adrenal glands may be a source of ET-3 detectable in human plasma, and its release might lead to further processing of Big ET-3 by smooth muscle cells inside the vasculature.

Among the endogenous isoforms of ET, ET-3 stands out because of its ability to differentiate between the two endothelin receptors. It binds to the ETB receptor much like ET-1 but has negligible or no affinity for the ETA subtype at normal doses. In humans, the majority of vasculature receptors are ETA receptors, and the vasoconstrictive effects are minimally affected by the low density of ETB receptors (<15%) on the smooth muscle of the vasculature. In the kidney, ETB receptors are the most common subtype, and they tend to cluster in areas without blood vessels. Emerging evidence suggests that the ETB sub-type removes ET from circulation by acting as a clearing receptor. An increase in circulating immunoreactive ET is the outcome of blocking the ETB receptor. A spike in ET-3 levels in the blood is a direct outcome of receptor antagonists blocking the ETB receptor. via triggering the release of opposing vasodilators via endothelial ETB receptors, ET-3 may minimize undesired vasoconstriction and have a positive function in human illness.

Endothelin moa

ET has a dual receptor profile, acting on both ETA and ETB. Besides narrowing blood vessels, ET-1 also makes vascular cells fibrose and increases ROS generation. The hypothesis put out is that ET-1 triggers processes that promote inflammation by increasing the formation of superoxide anion and cytokine release. The activation of transcription factors like NF-κB and the production of proinflammatory cytokines like TNF-α, IL-1, and IL-6 are both demonstrated by a recent research that involves ET-1. A number of animal species have shown an elevation in ET-1 plasma levels during endotoxaemia. According to some writers, there is a direct relationship between the level of endothelin in the blood and the incidence of illness and death in patients with septic shock.

The typical role of ET in healthy individuals is to keep the vasculature from becoming unstable. When it comes to ET, nitric oxide (NO) is the most crucial interaction. The endothelial nitric oxide synthase (eNOS) increases cyclic GMP by releasing NO following the consumption of L-arginine. In cases of endothelial dysfunction caused by inflammation or excessive oxidative stress, NO generation might become faulty. Abnormal NO metabolism and subsequent worldwide vasoconstriction can also be brought about by mental stress, rage, or cold. The NO synthase enzyme's ability to do its job is vulnerable to oxidative stress in any form. To keep the blood vessels open when NO isn't working properly, other processes involving prostacyclin, natriuretic peptide, and cytochrome-dependent components kick in. When a person is sick, their body's regulatory systems shift toward imbalanced vasoconstriction, which causes an increase in ET and a decrease in NO, which in turn causes vasoconstriction to be aided by COX-1 and COX-2 processes.

Endothelin function

(1) Fibrogenic effect

Many types of fibrosis are associated with elevated ET-1 concentrations in plasma and certain tissues. In bleomycin-induced lung fibrosis, for instance, there is an upregulation of ET-1 immunoreactivity and ECE-1 expression. The release of collagens I and III was also induced in fibroblasts from scleroderma skin lesions by ET-1. Last but not least, a transgenic animal overexpressing human preproET-1 developed renal fibrosis. When it comes to the heart, ET-1 directly promotes the proliferation of cardiac fibroblasts and myocardial fibrosis. It seems that there are several factors contributing to the fibrogenic impact of ET-1. There is evidence that ET-1 has direct effects on a wide variety of cellular processes, including proliferation, survival, and activation, as well as on the production of proteins involved in the extracellular matrix (such as fibronectin, collagen types I and III, and tissue inhibitors of matrix metalloproteinase) and the suppression of their degradation. The activation of certain fibrogenic effector cells is a common thread in the field of wound healing. This process occurs when inflammatory cells and other types of cells produce cytokines or aberrant extracellular fragments, which excite effector cells. Mesenchymal lineage constitutes the majority of the effector cells. In particular, there are fibroblasts in the epidermis and myofibroblasts in the heart, as well as hepatic stellate cells and mesangial cells in the liver and kidney, respectively. Surprisingly, the majority of these effectors are regulated autocrinely in some way. In a common autocrine loop, activated effector cells go on to generate cytokines, which in turn activate more effector cells.

(2) Regulate blood pressure

By raising vascular tone and encouraging vascular remodeling through its mitogenic action, ET-1 is recognized as a responsible party in the development of pulmonary hypertension (PH). There are gender disparities in the pathogenesis and prognosis of pulmonary arterial hypertension (PAH), despite the fact that the condition primarily affects females. This was proven by comparing the reactions of men and women to ET receptor-blockers, which showed that women had a far better response. In contrast, phosphodiesterase inhibitors were more effectively absorbed by men, revealing a pathophysiological sexual dimorphism.

The processes involved in the genesis of PH also divide it into subtypes; for example, thromboembolism-induced PH causes an increase in ETB levels. Patients in NYHA Classes 3 and 4 whose symptoms do not go away or are not responsive to immediate vasodilators can now be prescribed ET receptor blockers like bosentan (non-selective) or sitaxentan (selective) as a result of the discovery of these pathways.

(3) Regulate pathophysiologic activity in the kidney

The production of endothelin by the renal endothelium controls the excretion of both salt and water. Under conditions of volume overload, the endothelium experiences shear stress, which triggers the synthesis of ET-1. This protein then works on the thick ascending limb and collecting duct, reducing salt and water reabsorption through many routes and intermediates, such as nitric oxide. Research using ETA blockers demonstrated natriuresis via its action on the nephron, lending credence to this theory. Furthermore, ET-1 in the kidneys triggers the secretion of angiotensin-II, which in turn triggers a redox cascade that raises ET-1 expression. Proteinuria and glomerulosclerosis are the results of endothelin inducing podocyte glomerular damage through activation of ETB. The precise process is still not well known. One clinical and pathological phenomenon with an abnormal glomerular filtration barrier is Focal Segmental Glomerulosclerosis (FSGS). An increase in ET-1 urine excretion occurs during pathogenesis as well. This pattern of development is most commonly seen in the age-associated main FSGS subtype.

References

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