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Genetic Variation in the Endothelin System
Author(s) -
ROSSI GIAN PAOLO,
PITTER GISELLA
Publication year - 2006
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1196/annals.1351.004
Subject(s) - medicine , vasoconstriction , endocrinology , autocrine signalling , endothelin receptor , heart failure , endothelins , prostacyclin , endothelin 1 , pulmonary hypertension , receptor
Endothelin‐1 (ET‐1) exerts multiple biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET‐1 is synthesized by ET‐converting enzymes (ECE), chymases (CMAs), and non‐ECE metalloproteases through a process regulated in an autocrine fashion in vascular and nonvascular cells. ET‐1 acts through the activation of G i protein–coupled receptors. ET A receptors mediate vasoconstriction and cell proliferation, whereas ET B receptors are important for aldosterone secretion, endothelial cell (EC) migration, the release of nitric oxide (NO) and prostacyclin, the clearance of ET‐1, and the inhibition of ECE‐1 . ET is activated in scleroderma, hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because of the predominantly abluminal secretion of the peptide. Experimental studies and clinical trials have demonstrated that ET‐1 plays a major role in normal cardiovascular homeostasis and in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure. Accordingly, ET antagonists are promising new agents in the treatment of cardiovascular diseases. Single nucleotide polymorphisms (SNPs) of the genes of preproET‐1 , ECE‐1 , CMA, ET A and ET B receptors have been identified and can be important for their functional regulation. However, for most of them the association with disease conditions and the evidence for a functional role remain controversial. Thus, even though ET antagonists are being used for the treatment of pulmonary hypertension, there is no convincing evidence for a role of SNPs in affecting the therapeutic strategies.