Endothelin-1 was discovered, isolated and sequenced in 1988.
The endothelin system comprises 3 highly potent vasoconstrictor peptides:
Of clinical relevance is ET-1, which is produced by far the most. It binds to ETA and ETB receptors with significantly higher affinity than ET-2 or ET-3.
Mutations in the ET receptor genes(EDNRA + EDNRB) are associated with Hirschsprung's disease.
Endothelins are primarily formed by vascular endothelia. They are involved in complex regulatory mechanisms in various organs and exert a range of pharmacological effects.
The main production sites for endothelin-1 are the endothelial cells of the lung, but also epithelial cells, macrophages, granulocytes, macrophages, fibroblasts and osteoblasts. The release of ET-1 is regulated at the gene level. It is induced by thrombin, angiotensin II, adrenaline, cortisol, endotoxin, hypoxia, growth factors of T cells and macrophages.
Endothelin-1 is thought to be involved in the pathophysiology of acute renal failure, Raynaud's phenomenon, bronchial asthma, primary pulmonary hypertension and progressive systemic scleroderma.
Acute effects of the peptide ET-1 include strong vasoconstriction, platelet aggregation, fibrosis, vascular hypertrophy and inflammatory reactions. It can activate fibroblasts and macrophages and induce proliferation and procollagen synthesis in fibroblasts in addition to chemotaxis. The proliferation of endothelium, fibroblasts and vascular smooth muscle cells leads to vascular occlusion, necrosis and ulcers. Overexpression of ET-1 plays a crucial role in pulmonary arterial hypertension, collagenosis and pulmonary fibrosis. Elevated ET levels correlate with the severity and progression of the disease. Receptors for ET-1 have been abundantly detected in skin and pulmonary vessels.
Endothelin-1 is stimulated by UV-B radiation. The peptide is also produced by keratinocytes, among others. It promotes the proliferation, chemotaxis and melanin production of melanocytes. It also plays a decisive role in melanocyte homeostasis and migration (Haass NK et al. 2005).
Systemic scleroderma: Circulating functional autoantibodies directed against the vascular angiotensin II receptor type 1 and the endothelin-1 receptor type A have been reported and are thought to play a pathogenic role (Avouac J et al. 2015; Cabral-Marques O et al. 2017). However, their exact involvement in pathogenesis remains to be determined, and it is also not yet clear whether they can be used as biomarkers or even represent therapeutic targets.
Bosentan is an endothelin receptor antagonist.
Avouac J et al. (2015) Autoantibodies against endothelin 1 type a receptor are strong predictors of digital ulcers in systemic sclerosis. J Rheumatol 42: 1801-1807.
Cabral-Marques O et al. (2017) Functional autoantibodies targeting G protein-coupled receptors in rheumatic diseases. Nat Rev Rheumatol13: 648-656.
Haass NK et al. (2005) Normal human melanocyte homeostasis as a paradigm for understanding melanoma.
JInvestig Dermatol Symp Proc 10:153-163.