Journal
CIRCULATION
Volume 102, Issue 19, Pages 2434-2440Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.CIR.102.19.2434
Keywords
atherosclerosis; restenosis; heart failure; hypertension; transplantation; nitric oxide
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The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various 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 endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ETA receptors mediate vasoconstriction and cell proliferation, whereas ETB receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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