ET (endothelin)-1 was first described as a potent vasoconstrictor. Since then, many other deleterious properties mediated via its two receptors, ETA and ETB, have been described, such as inflammation, fibrosis and hyperplasia. These effects, combined with a wide tissue distribution of the ET system, its up-regulation in pathological situations and a local autocrine/paracrine activity due to a high tissue receptor binding, make the tissue ET system a key local player in end-organ damage. Furthermore, ET-1 interacts in tissues with other systems such as the RAAS (renin–angiotensin–aldosterone system) to exert its effects. In numerous genetically modified animal models, non-specific or organ-targeted ET-1 overexpression causes intense organ damage, especially hypertrophy and fibrosis, in the absence of haemodynamic changes, confirming a local activity of the ET system. ET receptor antagonists have been shown to prevent and sometimes reverse these tissue alterations in an organ-specific manner, leading to long-term benefits and an improvement in survival in different animal models. Potential for such benefits going beyond a pure haemodynamic effect have also been suggested by clinical trial results in which ET receptor antagonism decreased the occurrence of new digital ulcers in patients with systemic sclerosis and delayed the time to clinical worsening in patients with PAH (pulmonary arterial hypertension). The tissue ET system allows therapeutic interventions to provide organ selectivity and beneficial effects in diseases associated with tissue inflammation, hypertrophy or fibrosis.
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Review Article|
August 17 2010
At the heart of tissue: endothelin system and end-organ damage
Marc Iglarz;
Marc Iglarz
1
1Actelion Pharmaceuticals Limited, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
Correspondence: Dr Marc Iglarz (email [email protected]).
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Martine Clozel
Martine Clozel
1
1Actelion Pharmaceuticals Limited, Gewerbestrasse 16, CH-4123 Allschwil, Switzerland
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Publisher: Portland Press Ltd
Received:
April 21 2010
Revision Received:
June 30 2010
Accepted:
July 01 2010
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2010 Biochemical Society
2010
Clin Sci (Lond) (2010) 119 (11): 453–463.
Article history
Received:
April 21 2010
Revision Received:
June 30 2010
Accepted:
July 01 2010
Citation
Marc Iglarz, Martine Clozel; At the heart of tissue: endothelin system and end-organ damage. Clin Sci (Lond) 1 December 2010; 119 (11): 453–463. doi: https://doi.org/10.1042/CS20100222
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