Role of Endothelin‐1 in Atherosclerosis^a

Abstract

Increased evidence has shown that endothelin‐1 (ET‐1) derived from the arterial cells is involved in the development of atherosclerosis. ET‐1 and ET receptors are upregulated in both human and experimental animal atherosclerotic lesions. Plasma ET‐1 levels are significantly elevated in hypercholestolemic subjects and cholesterol‐fed animals. We hypothesized that plasma lipoproteins such as LDL and HDL retained in the arterial wall can affect ET‐1 production and secretion, thereby sustaining vascular functions. Using a two‐chamber culture system, we have demonstrated that endothelial cells (ECs) show a polar secretion of ET‐1; the majority of ET‐1 are secreted toward the basal side of the vessels. Furthermore, we found that LDL enhances whereas HDL inhibits the ET‐1 secretion from ECs in a polarized pattern. In order to demonstrate ET receptor distribution in the lesion, we recently studied both human and apoE‐KO mice. Our study showed that there is an increased expression of ETB receptors in foamy macrophages in the lesions. More importantly, medial smooth muscle cells (SMCs) beneath the foam cell lesions exhibited a higher intensity of ETB receptor immunoreactivity than those located in foam cell‐free areas. In such an area, ET‐1 immunoreactivity is also increased. These results suggest that accumulation of foamy macrophages may modulate the shift of ET receptor subtypes from ETA to ETB in SMCs and an enhanced ET system mediated by ETB receptors may play a pivotal role in the progression of atherosclerosis. This notion has been further supported by a recent finding that administration of ET receptor antagonists resulted in a significant reduction of atherosclerosis in apoE‐KO mice.

Low density lipoprotein induces upregulation of vasoconstrictive endothelin type B receptor expression

“…ET-1 overexpression exacerbates high-fat diet-induced atherosclerosis in apolipoprotein E knockout mice (Li et al, 2013b) and in patients with atherosclerosis (Fan et al, 2000;Iwasa et al, 1999). More interestingly, there is induced upregulation of vasoconstrictive ET B receptor expression on porcine coronary artery smooth muscle cells in diet-induced hypercholesterolemia (Hasdai et al, 1997), in smoke exposed rats and in hypertension (Li et al, 2007), ischemic cardiovascular disease (Wackenfors et al, 2004), ischemic stroke (Povlsen et al, 2012) as well as in suspected acute coronary syndrome in patients (Dimitrijevic et al, 2009).…”

Endothelium-derived endothelin-1

“…Hence, the functional contribution of ET-1 appears to rise with the severity of the disease. Raised plasma levels of ET-1 have been reported in patients with atherosclerosis, and upregulation of ET-1 and its receptors has been described in atherosclerotic arteries and plaques [64,67,80,81]. Big ET-1 and ET-1 immunoreactivity has been found in regions of atherosclerosis [79,82].…”

Endothelin-converting enzyme-1 increases in atherosclerotic mice: potential role of oxidized low density lipoproteins

“…Endothelin (ET) has been one of these mediators (12). In fact, increased circulating levels of ET-1 have been detected in patients with hypercholesterolemia (13,14).…”