Genetic Variation in the Endothelin System

Abstract

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.

Pharmacogenomics of G Protein-Coupled Receptor Ligands in Cardiovascular Medicine

“…Two subtypes of endothelin receptors exist, termed ET A and ET B , and several mutations and polymorphism have been described in the corresponding genes (Rossi and Pitter, 2006). Although some of the ET B receptor variants may be important in the pathogenesis of Hirschsprung's disease, there are also several reports linking them to cardiovascular disease, such as arterial and pulmonary hypertension or congestive heart failure, but many of these associations are not unequivocal or remain to be replicated (Rossi and Pitter, 2006).…”

Gene expression of endothelin receptors in replaced rheumatic mitral stenotic valves

“…The importance of ETs and its receptors for the pathogenesis of many diseases has been the subject of intense research since its discovery [13][14][15]. Those diseases that involve excessive vasoconstriction and cell proliferation have been an especial focus.…”

Amplificação dos genes que codificam a endotelina-1 e seus receptores em valvas mitrais reumáticas

“…They have multiple biological effects through their A and B receptors, and their tissue concentrations are more accurate reflection of endothelin system activation 4 . ET-1 may act as a link between vascular changes and collagen accelerated metabolism associated to fibrotic process under certain conditions 5 .…”