The role of endothelin in connective tissue diseases
Department of Dermatology, University of Erlang, Germany.
Correspondence to: M. Sticherling, Department of Dermatology, University of Erlang, Germany. E-mail: Michael.Sticherling{at}derma.imed.uni-erlangen.de
 |
Abstract |
|---|
 Top Abstract Endothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
Vascular dysregulation is centrally involved in the pathogenesis of diverse rheumatological diseases. The resulting pulmonary arterial hypertension as well as Raynaud's phenomenon may be accompanied by distinct tissue fibrosis. The pleiotropic cytokine endothelin may represent a link between these vascular and fibrotic processes, which are most evidently seen in systemic sclerosis. Among three closely related isoforms, endothelin-1 (ET-1) is the most common in humans, and is often referred to as ET in the literature. ET-1 is involved in physiological processes of vascular tone and mitogenesis, whereas under pathological conditions fibrosis, vascular hypertension and inflammation are induced. Its expression is dependent on tissue and cell type as well as on the underlying disease entity and its stage. Elevated plasma and tissue levels have been demonstrated in idiopathic pulmonary hypertension, systemic sclerosis as well as in other connective tissue diseases and correlate to haemodynamic parameters and disease outcome. The biological effects are mediated by two membrane receptors (ET-1-receptor A and B) belonging to the G-protein-coupled serpentine family. Both receptors are differentially expressed by different cell types as well as in different diseases entities. Antagonizing these receptors therapeutically has already been successful. However, the differential action of ET is counterbalanced by other mediators, prominently nitric oxide. Consequently, the suspected direct relation of vascular and fibrotic processes through ET still needs to be further evaluated.
|
Endothelin—a pleiotropic peptide |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
Vascular dysfunction is regarded to be a key mechanism within the pathogenesis of connective tissue diseases next to pathological changes within the collagen metabolism and the immune system [1]. All three parameters appear to be related, however, the sequence and relevance of their contribution is still a matter of debate. Vascular dysfunction is clinically evident as Raynaud's phenomenon as well as pulmonary arterial hypertension (PAH) [1]. However, close pathogenetic similarities seem to exist between different vascular abnormalities with a number of shared proteinaceous and lipid factors including prostacyclins and cytokines.
Among these, endothelin (ET) has been first identified in 1988 [2], and in the meantime it has been characterized as a pleiotropic cytokine with prominent vasoconstrictor activity [3, 4]. Three isoforms denominated ET-1 to -3 have been described to date. They are coded by individual genes with a typical tissue expression and function. Whereas the function of ET-2 has not been defined so far and ET-3 seems to be expressed predominantly within the nervous tissue, ET-1 represents the major isoform in humans, and is mostly referred to as ET in the literature. It is processed sequentially from a 212 amino acid pre-pro ET-1 through the 38 amino acid big ET-1 to the 21 amino acid biologically active ET-1 by an endopeptidase and the ET converting enzyme. The close homology to the vasoconstrictive snake venom peptide sarafotoxin is reflected by the prominent biological activity of ET.
|
Biological activity of endothelin |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
The biological activity of ET can result in acute and chronic effects under both physiological as well as pathological conditions [4], and reflect its characterization as both a cytokine and neurohormone. Under physiological conditions within the cardiovascular and respiratory system the vascular tone and mitogenesis are regulated whereas in pathological processes fibrosis, vascular hypertrophy as well as inflammation may result.
In vitro experiments with ET on the release of interleukin-6 showed dose-dependent effects of similar magnitude compared with tumour necrosis factor-
(TNF-), in addition to an increased vascular permeability of the trachea and upper respiratory tract and to a lower extent of the lower respiratory tract [4, 5].
Major biological effects include the induction of mitogenesis of fibroblasts, smooth muscle cells and myocytes, the induction of fibronectin as well as chemotaxis of fibroblasts [3, 4]. In addition, cytokine-like effects result in the activation of neutrophilic granulocytes and the release of intracytoplasmic elastase as well as mast cell and monocyte activation. Acute effects present as vasoconstriction, increased platelet aggregation, increase of vascular permeability as well as the induction of inflammatory processes. They are opposed to chronic effects resulting from increased cell proliferation and tissue fibrosis as well as neurohormone-like actions. These include the induction of angiotensin-II and norepinephrine as well as the production of corticosteroids (cortisol, corticosterone and aldosterone) by the adrenal glands. ET is further involved in the production of various products of the arachidonic acid metabolism relating its action to prostacyclins, which also play a central role in the pathogenesis of PAH. Consequently, ET-1 may represent the missing link between vascular and fibrotic processes in systemic sclerosis, a direct clinical association, however, needs further evaluation.
|
Expression of endothelin and its modulation |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
The protein was found expressed in the cardiovascular, gastrointestinal and urogenital tract as well as endocrine organs and the central nervous system. The expression is modulated by various endogenous as well as environmental factors of both chemical and physical nature, which exert their effects mainly through calcium-dependent protein kinases C (PKC) [3, 4]. Whereas stimulation is found by hypoxia, friction forces as well as angiotensin II and different cytokines, the expression is inhibited by nitric oxide as the major counteracting and regulatory substance in addition to natriuretic peptide and increased blood flow. Physiological plasma concentrations are as low as 1 fmol/ml with a half-life of the peptide ranging from 4 to 7 min only. Increased serum and tissue concentrations as found under pathological conditions may not, however, represent biologically active material when detected by ELISA.
|
Endothelin and specific disease conditions |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
Increased plasma levels have been found in systemic sclerosis with and without PAH, particularly diffuse disease, systemic lupus erythematosus and other connective tissue diseases including mixed connective tissue disease (Sharp syndrome) and dermatomyositis in addition to rheumatoid arthritis, Winiwarter-Buerger's disease as well as Takayasu arteriitis. Similar results were found for idiopathic PAH (IPAH) [3–6].
ET has been studied extensively regarding various aspects of systemic sclerosis where the levels of expression were found to correlate to clinical parameters that reflect vascular tone dysfunction [4, 6]. The mean plasma concentration in systemic sclerosis was found to be 1.8 pg/ml. When defining a limit of plasma concentration 4.3 pg/ml as prognostic factor for pulmonary hypertension, mean plasma levels above this value indicate a distinct increase of a lethal course of the disease at 12 months with a 48-month survival of only 20% as opposed to a 100% survival up to 20 months and subsequent decrease to 40% at month 48 with plasma levels above 4.3 pg/ml [7]. ET levels particularly correlate to the diffuse disease course, lung involvement, pulmonary hypertension and renal crisis [4, 6–8]. Whereas single ET levels do not allow an individual prognostic evaluation, overall ET plasma levels correlate statistically to the pulmonary vascular resistance as well as to the severity of PAH. Increased dermal tissue expression of ET-1 could be demonstrated in systemic sclerosis and increased pulmonary fibrosis in ET transfected mice as compared with control mice at the age of 12 months [9]. In addition to elevated plasma levels in systemic sclerosis, ET-1 was found to be increased in the bronchioalveolar lavage fluid of affected patients, within dermal blood vessels and interstitium of early diffuse skin lesions and was positively correlated to sclerosis-associated lung fibrosis [4].
|
Endothelin receptors |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
The biological effects of ET are mediated by specific cell surface receptors that belong to the family of G-protein-coupled serpentine receptors with seven transmembrane loops [10]. Two different receptors called ET-A and ET-B receptors (ETA, ETB) have been detected in humans with differing expression and activity profiles depending on the organ and cell type as well as on the disease entity and disease state. Whereas ETA is selective for ET-1, ETB can bind all three ET isoforms with similar affinity. ETA is found predominantly on vascular smooth muscle cells and mainly mediates vasoconstriction. Similar effects are mediated by ETB when expressed on smooth muscle cells, in contrast to endothelial cells where vasodilation predominates. In contrast to vasodilatory effects under physiological conditions, ETB may be vasoconstrictive under pathological conditions. Further differential effects may be seen in different disease states. In systemic sclerosis, ETB was found increased and ETA decreased in both fibrotic lung tissue and skin derived fibroblasts [4]. Altogether, the net clinical effects of ET are influenced by the tissue type and disease state as receptor number and activity may change. However, ET is not a solitary player, but is counter-balanced apart from prostacyclins by nitric oxide as one of the major mediators within this context [4, 11]. The fine tuning of the vasodilatory status of blood vessels is effected by both mediators under physiological conditions. It comprises nitric oxide release triggered by ET-1 through the ETB on endothelial cells which in turn suppresses ET-1 release. Disruption of this balance as seen in systemic sclerosis will result in an increased ET-1 production and consecutive obliterative vasculopathy [1, 4, 11].
Based on these data and the resulting concepts, a therapeutic blockade of ET receptor seems promising. Selective ETA and dual ETA/B antagonists have been evaluated in clinical studies and shown to be effective [12]. Among intravenous epoprostenol, inhaled iloprost as well as oral sildenafil bosentan, a dual ET-receptor antagonist that is applied orally, is regarded as the first-line component for the treatment of PAH [13]. In addition, recent placebo-controlled clinical study could demonstrate a decreased incidence of digital ulcers, whereas no effects were seen on the healing of already present ulcers [14]. However, bosentan has not yet been approved for the treatment of digital ulcers.
Studies on ET and its receptors still need to be scrutinized, especially to demonstrate a suspected direct relation of vasoconstrictive effects to tissue fibrosis. Apart from pathogenic insight, novel therapeutic approaches will be developed to stop the severity and progress of the grossly disabling diseases.
The author has received speaker's honorarium for participation at Actelion Winter School 2006.
|
References |
|---|
|
TopAbstractEndothelin--a pleiotropic...Biological activity of...Expression of endothelin and...Endothelin and specific disease...Endothelin receptorsReferences |
|---|
- Kahaleh MB. (2004) Vascular involvement in systemic sclerosis (SSc). Clin Exp Rheumatol 2:S19–23.
- Yanagisawa M, Kurihara H, Kimura S, et al. (1988) A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–5.[CrossRef][Medline]
- Masaki T. (2004) Historical review: endothelin. Trends Pharmacol Sci 25:219–24.[CrossRef][Medline]
- Mayes MD. (2003) Endothelin and endothelin receptor antagonists in systemic rheumatic disease. Arthritis Rheum 48:1190–9.[CrossRef][Web of Science][Medline]
- Browatzki M, Pfeiffer CA, Schmidt J, Kranzhofer R. (2005) Endothelin-1 induces CD40 but not IL-6 in human monocytes via the proinflammatory transcription factor NF-kappaB. Eur J Med Res 10:197–201.[Web of Science][Medline]
- Biondi ML, Marasini B, Bassani C, Agastoni A. (1991) Increased plasma endothelin levels in patients with Raynaud's phenomenon. New Engl J Med 324:1139–40.[Web of Science][Medline]
- Galie N, Manes A, Branzi A. (2004) The endothelin system in pulmonary arterial hypertension. Cardiovasc Res 61:227–37.[CrossRef][Web of Science][Medline]
- Teder P and Noble PW. (2000) A cytokine reborn? Endothelin-1 in pulmonary inflammation and fibrosis. Am J Respir Cell Mol Biol 23:7–10.
[Free Full Text] - Hocher B, Schwarz A, Fagan KA, et al. (2000) Pulmonary fibrosis and chronic lung inflammation in ET-1 transgenic mice. Am J Respir Cell Mol Biol 23:19–26.
[Abstract/Free Full Text] - Hosoda K, Nakao K, Tamura N, et al. (1992) Organization, structure, chromosomal assignment, and expression of the gene encoding the human endothelin-A receptor. J Biol Chem 267:18797–804.
[Abstract/Free Full Text] - Humbert M, Sitbon O, Simonneau G. (2004) Treatment of pulmonary arterial hypertension. New Engl J Med 351:1425–36.
[Free Full Text] - Hachulla E and Coghlan JG. (2004) A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism. Ann Rheum Dis 63:1009–14.
[Abstract/Free Full Text] - Rubin LJ, Badesch DB, Barst RJ, et al. (2002) Bosentan therapy for pulmonary arterial hypertension. New Engl J Med 346:896–903.
[Abstract/Free Full Text] - Korn JH, Mayes M, Matucci Cerinic M, et al. (2004) Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 50:3985–93.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||