Important facts about the endothelin family of peptides

by Elisakits BioSupply Manufacturer & Supplier

Endothelins are peptides that are responsible for causing the blood vessels to constrict which can lead to an increase in blood pressure. They are generally 21 amino acids in length, vasoconstricting peptides that are mainly formed in the endothelium and have an important role in the process of vascular homeostasis. The balance of the correct levels of endothelin is often maintained by many processes within the body, however, during period's of overexpression, this can result in high blood pressure (often also called hypertension), heart disease and the potential of a number of other diseases.

There are many diseases which have been associated to the ubiquitous distribution and the dysregulation of endothelin peptides or their receptors, for example:

Atrial or pulmonary hypertension and a number of other cardiovascular disorders.
Heart failure and cardiac hypertrophy.
Cerebral vasopressin due to subarachnoid hemorrhage.
Several other types of cancers.
Type II diabetes.
Hisrchsprung disease.
Dengue haemorrhagic fever.

At present there are three isoforms of the endothelin peptide that have discovered: endothelin 1 (ET-1), endothelin-2 (ET-2) and endothelin-3 (ET-3). These peptides are able to bind to four different endothelin receptors (essentially ET_A1, ET_B1, ET_B2 and ET_C) and can be present in various regions of the body.

Endothelin-1

Endothlin-1 (ET-1) is a 21 amino acid peptide that is encoded by the EDN1 gene in humans, it is produced by vascular endothelin cells and can also be referred to as preproendothelin-1 (PPET-1). Preproendothelin-1 is a precursor for the ET-1 peptide, where the endothelial cells are responsible for converting preproendothelin into proendothelin which is eventually released as mature endothelin. Endothelin-1 is regarded as a potent vasoconstrictor that can bind to the receptors of the smooth muscle endothelin (ET_A and ET_B receptors). ET-1 receptors in the heart are well known to be associated with calcium from the sarcoplasmic reticulum, this can lead to increased heart rate and contractility. Do to the properties of ET-1, it is widely implicated in the pathogenesis of heart failure, hypertension and coronary vasospasm.

Endothelin-2

Endothelin-2 (ET-2) is a secretory vasoconstrictive peptide which is essential in initiating intracellular signalling events via endothelin ligand receptors. The expression of ET-2 is predominately localised on the granulosa cells which are found in the follicles of murine, bovine and human ovarian tissues. One of the main role of endothelin-2 within the ovarian follicle has been found to be linked to ovulation, it is responsible for causing strong smooth muscle cell contractions in ovarian tissues, the production of ET-2 has been found to be at the highest levels just before ovulation.

Endothelin-3

Endothelin-3 (ET-3) is encoded by the EDN3 gene in humans, the active form of this protein is approx. 21 amino acid peptide which is derived from a precursor protein. The active form of endothelin 3 is able to interact with the endothelin receptor type B (EDNRB) and this interaction is critical in the development of many neural crest derived cell lineages for example enteric neurons and melanocytes. There is also evidence to suggest that any mutations to either the gene or the EDNRB can lead to Waardenburg syndrome and Hirschsprung disease, both of which are congenital disorders that are associated to neural crest derived cells.

Useful Further Reading

The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes. Proc Natl Acad Sci USA (1989) 86: 2863–2867. Inoue A., et al.
Endothelin: 20 years from discovery to therapy. Can J Physiol Pharmacol (2008) 86:485-498. Barton M. and Yanagisawa M.
Dissecting the complex physiology of endothelin: new lessons from genetic models. Hypertension (2010) 56:31-3. Pollock D.M.
Endothelin. Pharmacol Rev (2016) 68:357-418. Davenport A.P., et al.
Endothelin system: the double-edged sword in health and disease. Annu Rev Pharmacol Toxicol (2001) 41:851-76. Kedzierski R.M. and Yanagisawa M.