Endothelin-1 ET-1 is a 21 amino acid peptide that is produced by the vascular endothelium click here for details.
It is a very potent vasoconstrictor that binds to smooth muscle endothelin receptors, of which there are two subtypes: ET A and ET B receptors. These receptors are coupled to a Gq-protein and receptor activation leads to the formation of IP 3 , which causes the release of calcium by the sarcoplasmic reticulum SR and increased smooth muscle contraction and vasoconstriction.
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There are also ET B receptors located on the endothelium that stimulate the formation of nitric oxide , which produces vasodilation in the absence of smooth muscle ET A and ET B receptor activation. This receptor distribution helps to explain the phenomenon that ET-1 administration causes transient vasodilation initial endothelial ET B activation and hypotension, followed by prolong vasoconstriction smooth muscle ET A and ET B activation and hypertension.
ET-1 receptors in the heart are also linked to the Gq-protein and IP 3 signal transduction pathway click here for details. Therefore, ET-1 in the heart causes SR release of calcium, which increases contractility. ET-1 also increases heart rate. Because of its powerful vasoconstrictor properties, and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension , coronary vasospasm , and heart failure.
A number of studies suggest a role for ET-1 in pulmonary hypertension, as well as in systemic hypertension.
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ET-1 has been shown to be released by the failing myocardium where it can contribute to cardiac calcium overload and hypertrophy. Among these diseases, chronic heart failure, essential hypertension and pulmonary hypertension are being investigated extensively. Thus, ET is now recognized as being involved in the pathological process of vascular diseases. The production of ET and nitric oxide is regulated by the condition of the endothelium. In endothelial dysfunction, the production of nitric oxide is downregulated.
In contrast, the production of ET is upregulated. This yin and yang relationship of ET and nitric oxide production maintains the homeostasis of the vascular beds under physiological conditions. Any imbalance of this homeostasis promotes the pathological process of the vascular diseases at their primary stage, leading to a decrease in antithrombotic activity, and an increase in vascular tone and permeability and in cell growth activity. What kind of factor induces endothelial dysfunction?
Numerous reports have suggested the generation of reactive oxygen species ROS and an increased level of oxidative low-density lipoprotein oxLDL as important pathogenic factors. It is generally accepted that the oxidatively modified form of LDL is implicated in the pathogenesis of atherosclerosis 32 ; OxLDL is taken up into the macrophages and smooth muscle cells, and changes these cells into foam cells, leading to the formation of atheroma.
Similarly, oxLDL was also demonstrated to be taken up by endothelial cells. The known oxLDL receptors detected in macrophages or smooth muscle cells cannot be detected in endothelial cells. In , Kugiyama et al. Non-oxidized LDL does not induce impairment in the presence of an antioxidative reagent, although a previous report showed slight impairment of native LDL in the absence of an antioxidant.
These results showed that native LDL is oxidized during an interaction with oxygen, and ROS possibly activates endothelial cells via endothelial receptive sites for oxLDL, leading to endothelial dysfunction, i. These results suggest that the endothelial cell has a specific receptor for oxLDL, which does not react to native LDL. LOX-1 is expressed at a low level in a statical condition of endothelial cells, but is induced by proinflammatory cytokines and vasoconstrictive peptides in vitro and in proatherogenic conditions in vivo , such as hypertension, diabetes and hyperlipidemia.
In , Cominacini et al.
Disruption of vascular homeostasis via endothelial LOX Activation of LOX-1 also induces expression of chemokines and adhesive molecules, resulting in macrophage infiltration into the vascular wall and thrombus formation. LOX-1 expressed in the endothelial cell was shown to bind also to platelets, leading to a phenotype change of the endothelium as with oxLDL. This endothelial activation was also blocked by anti-LOX-1 antibody. Importantly, LOX-1 is now known as a novel adhesive molecule involved in leukocyte recruitment and inflammation that further increases oxidative stress.
In a model of low-dose endotoxin-induced uveitis, leucocytes interacted with and bind to the inner wall of the retinal vein. Actually, recombinant LOX-1 protein binds leukocytes in vitro in a flow condition. These properties of LOX-1 can be understood to change endothelial function, which increases prothrombotic and proinflammatory activity. ET was initially identified as a novel endothelial vasoconstrictor. The vascular endothelial cell exclusively produces ET Recently, ET-1 was recognized as an aggravating factor in several cardiovascular diseases, interacting with LOX-1, a novel endothelial receptor for oxLDL.
LDL is oxidized under oxidative stress. The increase in superoxide anions accelerates inactivation of NO. The reduction in NO and production of ET by oxLDL in the endothelial cell generates and promotes vascular diseases, such as atherosclerosis. In this process, LOX-1 plays a pivotal role in changing endothelial functions, such as prothrombotic and proinflamatory activity. So far, accumulating evidence has shown the involvement of LOX-1 in vascular diseases, including atherosclerosis, arteriosclerosis after cardiac transplantation, restenosis after percutaneous transluminal coronary angioplasty PTCA , myocardial infarction, angina pectoris, thrombosis and inflammation, including arthritis and uveitis.
Interestingly, the plasma ET-1 level increases in these diseases. These factors aggravate vascular diseases. Tomoh Masaki was born in These results were highly motivating in the study of the molecular biology of muscle. The whole primary sequence of several muscle proteins, including smooth muscle myosin heavy chain, was determined at his laboratory. During this period, he focused mostly on the investigation of smooth muscle.
In , an endothelial receptor for oxLDL was found in his laboratory at Kyoto. These vasoactive factors are thought to play important roles in physiology and pathophysiology of vascular beds, Therefore many investigators in the world are now interested in this problem. In , he assumed the position of President, at Osaka Seikei University. National Center for Biotechnology Information , U.
Find articles by Tomoh Masaki. Find articles by Tatsuya Sawamura. Author information Article notes Copyright and License information Disclaimer. Communicated by Masanori O tsuka , m. Received Oct 17; Accepted Nov This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This article has been cited by other articles in PMC.
Abstract Nitric oxide NO and endothelin ET produced in endothelial cells are leading molecules which regulate vascular function. Open in a separate window. Unique biosynthetic pathway of ET Sequence analysis of porcine ET-1 predicted that mature ET-1 is generated from a precursor via an unusual, previously unknown, proteolytic processing pathway.
Identification of the ET receptor At the early stage of ET research, dissociation of the potency order of the three ET isopeptides was reported in a variety of systems. Inhibitor of the ET system Since ET showed a potent vasoconstriction in isolated vascular beds and elicited unique sustained and elevated blood pressure when it was injected intravenously into animals, ET-1 was thought to play an important role in the maintenance of blood pressure.
Physiological significance of ET Because of its unique pharmacological properties, most investigators have thought that the ET-system plays an important role in the maintenance of blood pressure, as does the renin-angiotensin system. Pathophysiological significance of ET in the cardiovascular system It is now recognized that ET plays crucial roles in several cardiovascular diseases, including chronic heart disease, ischemic heart disease, hypertension, atherosclerosis, pulmonary hypertension, chronic heart failure and cerebrovascular spasm after subarachnoid hemorrhage.
Endothelial dysfunction and vascular diseases Thus, ET is now recognized as being involved in the pathological process of vascular diseases. Conclusion ET was initially identified as a novel endothelial vasoconstrictor.
Profile Tomoh Masaki was born in References 1. Furchgott R. Nature , — Hickey K.
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