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Life Sciences Nov 2014Twenty-five years ago, a groundbreaking paper from Tsukuba University in Japan was published, identifying the sequence of the endothelin gene and peptide (Nature 332,...
Twenty-five years ago, a groundbreaking paper from Tsukuba University in Japan was published, identifying the sequence of the endothelin gene and peptide (Nature 332, 411-415, 1988). This work opened the way for the discovery of the endothelin receptors and the development of orally active endothelin receptor antagonists (ERAs). Today, ERAs are part of medical therapy of patients around the world for the treatment of pulmonary arterial hypertension. Since the discovery of endothelin, about 1000 papers per year have been published, with more than 27,000 articles available today. Many important and break-through findings presented in the endothelin conferences have been published in the conferences' proceedings. Endothelin XIII is the proceedings of the Thirteenth International Conference on Endothelin, held at Tokyo Campus of Tsukuba University, Japan, in September 2013. At the conference, the 25th anniversary of endothelin's discovery was celebrated and articles produced from data presented at the conference are compiled in this Special Issue of Life Sciences. Endothelin XIII includes more than fifty articles, including review articles by experts in the field and numerous original research articles. As the Editors of this special issue, we are proud to present Endothelin XIII and wish the field continued growth for the benefit of patients and for the advancement of biomedical science.
Topics: Aging; Endothelins; Humans; MicroRNAs; Receptors, Endothelin
PubMed: 25264369
DOI: 10.1016/j.lfs.2014.09.021 -
Life Sciences Oct 2012Following the initial description of endothelium-dependent vasoconstriction in the early 1980s, it has been exactly 25 years since efforts to identify the sequence of...
Following the initial description of endothelium-dependent vasoconstriction in the early 1980s, it has been exactly 25 years since efforts to identify the sequence of the endothelin gene and peptide began in May 1987, work which resulted in a landmark paper submitted to Nature in December 1987 and published on March 31, 1988. The paper opened an entirely new field of research, followed by the inception of the International Conferences of Endothelin, the first of which was organized by Sir John Vane as Chair and held as the "First William Harvey Workshop on Endothelin" in London, UK, in December of 1988. Endothelin receptor antagonism has now been firmly established for more than a decade as a new, orally active drug treatment for patients with pulmonary arterial hypertension. Since the discovery of endothelin, on average 1,000 papers per year have been published with more than 25,000 papers available today, many of them published in the conferences' Proceedings. The present issue of Life Sciences, Endothelin XII, represents a collection of papers of original research and invited lectures presented at the Twelfth International Conference on Endothelin held in Cambridge, UK, in September 2011.
Topics: Drug Design; Endothelin Receptor Antagonists; Endothelins; Endothelium, Vascular; Familial Primary Pulmonary Hypertension; History, 20th Century; History, 21st Century; Humans; Hypertension, Pulmonary; Receptors, Endothelin; Vasoconstriction
PubMed: 22842029
DOI: 10.1016/j.lfs.2012.07.016 -
Cellular and Molecular Life Sciences :... Jan 2011Endothelin-1 is the most potent vasoconstrictor agent currently identified, and it was originally isolated and characterized from the culture media of aortic endothelial... (Review)
Review
Endothelin-1 is the most potent vasoconstrictor agent currently identified, and it was originally isolated and characterized from the culture media of aortic endothelial cells. Two other isoforms, termed endothelin-2 and endothelin-3, were subsequently identified, along with structural homologues isolated from the venom of Actractapis engaddensis known as the sarafotoxins. In this review, we will discuss the basic science of endothelins, endothelin-converting enzymes, and endothelin receptors. Only concise background information pertinent to clinical physician is provided. Next we will describe the pathophysiological roles of endothelin-1 in pulmonary arterial hypertension, heart failure, systemic hypertension, and female malignancies, with emphasis on ovarian cancer. The potential intervention with pharmacological therapeutics will be succinctly summarized to highlight the exciting pre-clinical and clinical studies within the endothelin field. Of note is the rapid development of selective endothelin receptor antagonists, which has led to an explosion of research in the field.
Topics: Aspartic Acid Endopeptidases; Cardiovascular Diseases; Clinical Trials as Topic; Endothelin Receptor Antagonists; Endothelin-Converting Enzymes; Endothelins; Familial Primary Pulmonary Hypertension; Female; Heart Failure; Humans; Hypertension, Pulmonary; Metalloendopeptidases; Ovarian Neoplasms; Receptors, Endothelin; Vasoconstriction
PubMed: 20848158
DOI: 10.1007/s00018-010-0518-0 -
British Journal of Pharmacology Jan 2013This themed section of the British Journal of Pharmacology contains reviews on recent developments in endothelin research arising from the Twelfth International...
UNLABELLED
This themed section of the British Journal of Pharmacology contains reviews on recent developments in endothelin research arising from the Twelfth International Conference on Endothelin (ET-12). It includes the emerging role for endothelin-2 in the cardiovascular system, ovarian development, immunology and cancer. The action of endothelin on two key targets is discussed: the paracrine or autocrine regulation of contractility and growth in the heart and the role of endothelin in renal disease. Epidemiological studies have demonstrated cardiovascular disease and circulating levels of endothelin-1 are lower in premenopausal women than in men and evidence is presented for the contribution of sex differences in responses to the peptide. Transcription is the primary level of regulation of the endothelin gene; and current research on the epigenetic regulation of the endothelin pathway, including the silencing of the EDNRB gene encoding the ET(B) receptor during tumourigenesis, is reviewed.
LINKED ARTICLES
This article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.168.issue-1. To view the previously published paper by Dhaun et al. visit http://dx.doi.org/10.1111/j.1476-5381.2012.02070.x.
Topics: Animals; Endothelins; Humans
PubMed: 23278331
DOI: 10.1111/bph.12022 -
Seminars in Nephrology Mar 2015Endothelin (ET) is one of the most potent renal vasoconstrictors. Endothelin plays an essential role in the regulation of renal blood flow, glomerular filtration, sodium... (Review)
Review
Endothelin (ET) is one of the most potent renal vasoconstrictors. Endothelin plays an essential role in the regulation of renal blood flow, glomerular filtration, sodium and water transport, and acid-base balance. ET-1, ET-2, and ET-3 are the three distinct endothelin isoforms comprising the endothelin family. ET-1 is the major physiologically relevant peptide and exerts its biological activity through two G-protein-coupled receptors: ET(A) and ET(B). Both ET(A) and ET(B) are expressed by the renal vasculature. Although ET(A) are expressed mainly by vascular smooth muscle cells, ET(B) are expressed by both renal endothelial and vascular smooth muscle cells. Activation of the endothelin system, or overexpression of downstream endothelin signaling pathways, has been implicated in several pathophysiological conditions including hypertension, acute kidney injury, diabetic nephropathy, and immune nephritis. In this review, we focus on the effects of endothelin on the renal microvasculature, and update recent findings on endothelin in the regulation of renal hemodynamics.
Topics: Endothelins; Glomerular Filtration Rate; Humans; Microcirculation; Renal Circulation
PubMed: 25966346
DOI: 10.1016/j.semnephrol.2015.02.004 -
International Journal of Molecular... Jul 2023Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent... (Review)
Review
Discovered almost 40 years ago, the potent vasoconstrictor peptide endothelin-1 (ET-1) has a wide range of roles both physiologically and pathologically. In recent years, there has been a focus on the contribution of ET-1 to disease. This has led to the development of various ET receptor antagonists, some of which are approved for the treatment of pulmonary arterial hypertension, while clinical trials for other diseases have been numerous yet, for the most part, unsuccessful. However, given the vast physiological impact of ET-1, it is both surprising and disappointing that therapeutics targeting the ET-1 pathway remain limited. Strategies aimed at the pathways influencing the synthesis and release of ET-1 could provide new therapeutic avenues, yet research using cultured cells in vitro has had little follow up in intact ex vivo and in vivo preparations. This article summarises what is currently known about the synthesis, storage and release of ET-1 as well as the role of ET-1 in several diseases including cardiovascular diseases, COVID-19 and chronic pain. Unravelling the ET-1 pathway and identifying therapeutic targets has the potential to treat many diseases whether through disease prevention, slowing disease progression or reversing pathology.
Topics: Humans; Cardiovascular Diseases; COVID-19; Endothelin-1; Endothelins; Chronic Pain
PubMed: 37511055
DOI: 10.3390/ijms241411295 -
Canadian Journal of Physiology and... Jul 2022Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular... (Review)
Review
Endothelin has emerged as a target for therapeutic intervention in systemic hypertension. As a vasoconstrictor, comitogenic agent, linking pulse pressure and vascular remodeling, and mediator of aldosterone and catecholamine release, endothelin is a key player in hypertension and end-organ damage. In 10%-20% of the hypertensive population, the high blood pressure is resistant to administration of antihypertensive drugs of different classes in combination. Because endothelin is not targeted by the current antihypertensive drugs, this may suggest that this resistance is due, in part at least, to a dependence on endothelin. This hypothesis is supported by the observation that this form of hypertension is often salt-sensitive, and that the endothelin system is stimulated by salt. In addition, the endothelin system is activated in subjects at risk of developing resistant hypertension, such as African Americans or patients with obesity or obstructive sleep apnea. Aprocitentan is an investigational, novel, potent, dual endothelin receptor antagonist (ERA) currently in phase 3 development for the treatment of difficult-to-treat hypertension. This article discusses the research that underpinned the discovery of this ERA and the choice of its first clinical indication for patients with forms of hypertension that cannot be well controlled with classical antihypertensive drugs.
Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Humans; Hypertension; Pyrimidines; Receptor, Endothelin A; Sulfonamides
PubMed: 35245103
DOI: 10.1139/cjpp-2022-0010 -
The Journal of Pain Jan 2009The endogenous endothelin (ET) peptides participate in a remarkable variety of pain-relatedprocesses. Pain that is elevated by inflammation, by skin incision, by cancer,... (Review)
Review
UNLABELLED
The endogenous endothelin (ET) peptides participate in a remarkable variety of pain-relatedprocesses. Pain that is elevated by inflammation, by skin incision, by cancer, during a Sickle Cell Disease crisis and by treatments that mimic neuropathic and inflammatory pain and are all reduced by local administration of antagonists of endothelin receptors. Many effects of endogenously released endothelin are simulated by acute, local subcutaneous administration of endothelin, which at very high concentrations causes pain and at lower concentrations sensitizes the nocifensive reactions to mechanical, thermal and chemical stimuli.
PERSPECTIVE
In this paper we review the biochemistry, second messenger pathways and hetero-receptor coupling that are activated by ET receptors, the cellular physiological responses to ET receptor activation, and the contribution to pain of such mechanisms occurring in the periphery and the CNS. Our goal is to frame the subject of endothelin and pain for a broad readership, and to present the generally accepted as well as the disputed concepts, including important unanswered questions.
Topics: Animals; Endothelins; Humans; Hyperalgesia; Models, Biological; Pain; Receptors, Endothelin; Signal Transduction
PubMed: 19111868
DOI: 10.1016/j.jpain.2008.09.009 -
Physiological Research Jun 2018The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic... (Review)
Review
The global epidemic of diabetes is of significant concern. Diabetes associated vascular disease signifies the principal cause of morbidity and mortality in diabetic patients. It is also the most rapidly increasing risk factor for cognitive impairment, a silent disease that causes loss of creativity, productivity, and quality of life. Small vessel disease in the cerebral vasculature plays a major role in the pathogenesis of cognitive impairment in diabetes. Endothelin system, including endothelin-1 (ET-1) and the receptors (ET(A) and ET(B)), is a likely candidate that may be involved in many aspects of the diabetes cerebrovascular disease. In this review, we took a brain-centric approach and discussed the role of the ET system in cerebrovascular and cognitive dysfunction in diabetes.
Topics: Animals; Brain; Cerebrovascular Circulation; Diabetes Complications; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelins; Humans; Receptor, Endothelin A; Receptor, Endothelin B
PubMed: 29947530
DOI: 10.33549/physiolres.933833 -
Life Sciences Oct 2012Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic... (Review)
Review
Endothelin-1 (ET-1) is a multifunctional hormone which regulates the physiology of the cardiovascular and renal systems. ET-1 modulates cardiac contractility, systemic and renal vascular resistance, salt and water renal reabsorption, and glomerular function. ET-1 is responsible for a variety of cellular events: contraction, proliferation, apoptosis, etc. These effects take place after the activation of the two endothelin receptors ET(A) and ET(B), which are present - among others - on cardiomyocytes, fibroblasts, smooth muscle and endothelial cells, glomerular and tubular cells of the kidney. The complex and numerous intracellular pathways, which can be contradictory in term of functional response depending on the receptor type, cell type and physiological situation, are described in this review. Many diseases share an enhanced ET-1 expression as part of the pathophysiology. However, the use of endothelin blockers is currently restricted to pulmonary arterial hypertension, and more recently to digital ulcer. The complexity of the endothelin system does not facilitate the translation of the molecular knowledge to clinical applications. Endothelin antagonists can prevent disease development but secondary undesirable effects limit their usage. Nevertheless, the increasing understanding of the effects of ET-1 on the cardiac and renal physiology maintains the endothelin system as a promising therapeutic target.
Topics: Animals; Cardiovascular Diseases; Cardiovascular System; Endothelin-1; Endothelins; Humans; Kidney; Kidney Diseases; Receptor, Endothelin A; Receptor, Endothelin B
PubMed: 22480517
DOI: 10.1016/j.lfs.2012.03.026