Endothelin: emerging role in diabetic vascular complications

Abstract

The endothelin (ET) family consists of three 21-amino acid peptides designated ET-1, 2]. The biological actions of the ETs are primarily mediated by two distinct, G-protein-coupled receptor subtypes designated ET A and ET B [2]. Endothelin A receptors have a higher affinity for ET-1 and ET-2 than ET-3 and the ET B receptor binds all three isoforms with equal affinity. Translation of preproET mRNA generates preproET, which is converted to big ET and finally cleaved by ET converting enzyme (ECE) to facilitate production of biologically active peptide. Endothelin-1 released by vascular endothelial cells exerts an autocrine influence by promoting vasodilatation, subsequent to activation of ET B receptors located on endothelial cells. It also exerts a paracrine effect on adjacent vascular smooth muscle cells (VSMC) in evoking vasoconstrictor and mitogenic actions by activation of both ET A and ET B receptors. The primary target of ET-1 is the vasculature where it evokes transient vasodilatation mediated by endothelial ET B receptors, followed by slow-onset and sustained contraction mediated by ET A and ET B receptors located on VSMC. The functional response to ET-1 varies throughout different tissues and vascular beds due to differences in distribution and expression of these two receptor subtypes. Endothelin-1 Diabetologia (1999) AbstractSince the discovery of endothelin-1 as the most potent endothelial-derived vasoconstrictor/mitogenic peptide a decade ago, considerable evidence has implicated this peptide in various cardiovascular disease states, including diabetes mellitus. Plasma and tissue concentrations of endothelin-1 as well as responses to the peptide are changed in various forms of the disease in humans and animals. Endothelin activity is also altered in atherosclerotic and ischaemic disease, nephropathy, retinopathy, erectile dysfunction, and neuropathy, many of the well-known complications of diabetes. Striking new evidence shows that antagonists of the endothelin system might beneficially affect and potentially overcome some of these complications. Despite this, lack of direct proof of causation makes this peptide's role in the disease uncertain. This review examines the current state of thought on the role of endothelin in diabetes and in the complications of the disease as well as the likely roles of altered metabolic variables in modulating endothelin-1 concentrations and its activity. It is concluded that although alterations in endothelin-1 release and action are clearly associated with the diabetic state, further studies using inhibitors of the endothelin system are warranted to determine its precise role in the complications of the disease. [Diabetologia (1999

Neurohormonal profile of patients with heart failure and diabetes

“…24,25 The endothelin system is also affected in patients with diabetes, and elevated levels of endothelin have been reported. 26 In HF, however, haemodynamic alterations and abnormalities primarily drive the increased neurohormonal activation, 9 and although all neurohormones were increased in the present study, parameters of the renin-angiotensin-aldosterone system as well endothelin were not increased in diabetic HF patients compared with HF patients without diabetes.…”

Evaluation of biochemical and clinical markers of endothelial dysfunction and their correlation with urinary albumin excretion in patients with type 1 diabetes mellitus

“…There is scarce data in the literature about the level of ET1 in T1DM patients compared to controls and the correlation between ET-1 and UAE rate. Most of the studies were conducted with T2DM patients and there are conflicting results suggesting that ET-1 level is not changed, increased or even decreased in diabetics (26)(27)(28). Those contradictory results might be arising from the heterogeneous group of patients in different study populations in regard to duration of diabetes or degree of glycemic control.…”

Increased contractility of diabetic rabbit corpora smooth muscle in response to endothelin is mediated via Rho-kinase β

“…7 One molecule that has been receiving much attention recently in the diabetic research community is endothelin. 8 The endothelins (ETs) are a family of 21-amino acid peptides consisting of ET-1, ET-2 and ET-3, 9 each the product of a separate gene and differing from one another by only a few amino acids. 10 Relative expression of the ET isoforms varies in different tissues, 11 with the biological actions of the ETs being determined by their relative binding to ET receptor subtypes.…”