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Review
. 2014 Jun 18;2014(2):62-78.
doi: 10.5339/gcsp.2014.29. eCollection 2014.

The role of endothelin-1 in pulmonary arterial hypertension

Adrian H Chester  1 , Magdi H Yacoub  2
Affiliations
Review

The role of endothelin-1 in pulmonary arterial hypertension

Adrian H Chester et al. Glob Cardiol Sci Pract. .

Abstract

Pulmonary arterial hypertension (PAH) is a rare but debilitating disease, which if left untreated rapidly progresses to right ventricular failure and eventually death. In the quest to understand the pathogenesis of this disease differences in the profile, expression and action of vasoactive substances released by the endothelium have been identified in patients with PAH. Of these, endothelin-1 (ET-1) is of particular interest since it is known to be an extremely powerful vasoconstrictor and also involved in vascular remodelling. Identification of ET-1 as a target for pharmacological intervention has lead to the discovery of a number of compounds that can block the receptors via which ET-1 mediates its effects. This review sets out the evidence in support of a role for ET-1 in the onset and progression of the disease and reviews the data from the various clinical trials of ET-1 receptor antagonists for the treatment of PAH.

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Figures

Figure 1.
Figure 1.
Characteristic histlogical changes seen in the pulmaonray areriesof lungs affected with PAH showing (A) medial hypertrophy, (B) concentric non-laminar intinal fribrosis, (C) eccentric intimal fibrosis, (D) thrombotic lesions, (E) concentric laminar intimal fibrosis, (F) plexiform lesions of small sinusoid-like vessesls, (G)multiple dilation lesions associated with centrally located plexiform lesions and (H) presence of T-lymphocytes (CD-3 positive) cells in a plexifrom lesion). From Montani el al.
Figure 2.
Figure 2.
Amino-acid structure of isoforms of endothelin. Chnages in specfic aminio acids in the peptide sequence compared to ET-1 circled in red.
Figure 3.
Figure 3.
Steps in the biosynthesis of endothelin-1. Modified from Kohan et al.
Figure 4.
Figure 4.
Endothelin receptor agoinsts, receptor subtypes and principal signalling pathways.
Figure 5.
Figure 5.
Interaction between endothelial cells and vascualar smooth mucle cells mediated by endothein-1. (NO, nitric oxide; ET-1, endothelin-1; cGMP, cyclic guanosine monophosphate; CA2+, calcium ions; PKC, protein kinase C; PI3-K, phosphatidylinositol 3-kinase; AKt – Protein Kinase B; MAPK, mitogen activated protein kinase). Modified from Kohan et al.
Figure 6.
Figure 6.
Signalling pathways linked to the conractile, migartory, proliverative and fate of cells mediated by ETA and ETB receptors. (PLC, phospholipase C; IP3, phosphatidylinositol; DAG, diacylglycerol; IP3 Ca2+, calcium ions; PKC, protein kinase C; MAPK, mitogen-activated protein kinase; PLD, phospholipase D; RTK, receptor tyrosine kinase; PI3K, phosphatidylinositol 3-kinase, cSRC, cytosolic tyrosine kinase; SHC, Src homology 2 domain-containing; GRB2, Growth factor receptor-bound protein 2; and SOS, Son of sevenless proetin; RAS, rat sarcoma protein; RAF, Rapidly Accelerated Fibrosarcoma protein).
Figure 7.
Figure 7.
Chemical stucture of clinically used endothein receptor antagonists.
Figure 8.
Figure 8.
Principal steps in the chemical synthesis of macitentan from bosentan.
See this image and copyright information in PMC

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