Endothelium-derived endothelin-1

Abstract

One year after the revelation by Dr. Furchgott in 1980 that the endothelium was obligatory for acetylcholine to relax isolated arteries, it was clearly shown that the endothelium could also promote contraction. In 1988, Dr. Yanagisawa's group identified endothelin-1 (ET-1) as the first endothelium-derived contracting factor. The circulating levels of this short (21-amino acid) peptide were quickly determined in humans, and it was reported that, in most cardiovascular diseases, circulating levels of ET-1 were increased, and ET-1 was then tagged as "a bad guy." The discovery of two receptor subtypes in 1990, ET(A) and ET(B), permitted optimization of the first dual ET-1 receptor antagonist in 1993 by Dr. Clozel's team, who entered clinical development with bosentan, which was offered to patients with pulmonary arterial hypertension in 2001. The revelation of Dr. Furchgott opened a Pandora's box with ET-1 as one of the actors. In this brief review, we will discuss the physiological and pathophysiological role of endothelium-derived ET-1 focusing on the regulation of the vascular tone, and as much as possible in humans. The coronary bed will be used as a running example in this review because it is the most susceptible to endothelial dysfunction, but references to the cerebral and renal circulation will also be made. Many of the cardiovascular complications associated with aging and cardiovascular risk factors are initially attributable, at least in part, to endothelial dysfunction, particularly dysregulation of the vascular function associated with an imbalance in the close interdependence of nitric oxide and ET-1.

Vasoregulatory peptides pro-endothelin-1 and pro-adrenomedullin are associated with metabolic syndrome in the population-based KORA F4 study

“…The observed strong relation between plasma levels of CT-proET-1 and MR-proADM suggests an interconnection between both polypeptide hormones. ET-1 is thought to be a key mediator in the pathogenesis of hypertension, macrovascular diseases, and diabetic microangiopathy, whereas ADM acts through vasodilation, natriuresis, and NO production (4,23). There is evidence from in vitro studies that ET-1 stimulates interleukin 6 secretion and downregulates adiponectin expression (30).…”

“…ET-1 is a 21-amino acid peptide secreted by vascular endothelium and represents one of the most potent vasoconstrictors by directly targeting endothelial cells and vascular smooth muscle cells and by inhibition of nitric oxide (NO) formation (3,4). ET-1 is derived from pre-pro-ET that undergoes cleavage by endopeptidases to form inactive precursors pro-ET, which is further cleaved by ET-converting enzyme to the active form.…”

Endothelin Receptor Signaling: New Insight Into Its Regulatory Mechanisms

“…Activation of ET A R and ET B R mediates many important functions, including vasoconstriction, cardiovascular remodeling, cell proliferation, cell differentiation, extracellular matrix production, and control of water and sodium secretion (4 -6). Although the pathophysiological role of ET A R and ET B R has not yet been completely elucidated, ET A R is considered as a bad receptor involved in pathogenesis and development of various diseases such as systemic and pulmonary hypertension, atherosclerosis, diabetes, and cardiac remodeling after myocardial ischemia (4,6,7). On the other hand, ET B R has been classified as a good receptor since it functions as a "clearance receptor" to prevent ET-1 from excessively stimulating ET A R and enhances endothelial production of nitric oxide (NO) and prostacyclin (PGI 2 ) to cause vasodilatation (7).…”

Correlation Between Endothelial Dysfunction and Left Ventricular Remodeling in Patients with Chronic Kidney Disease

“…In fact, the mechanism of endothelial dysfunction needs to be investigated deeply. The role of a decrease in nitric oxide (NO) and increase in endothelin-1 (ET-1) were thought to be one of the important mechanisms and manifestations of endothelial dysfunction in many diseases [5,6,7], including CKD [8]. …”