Canadian Journal of Physiology and Pharmacology

Endothelin: 20 years from discovery to therapy.(Clinical report)

Abstract: Since its identification as an endothelial cell-derived vasoconstrictor peptide in 1988, endothelin-1, the predominant member of the endothelin peptide family, has received considerable interest in basic medical science and in clinical medicine, which is reflected by more than 20000 scientific publications on endothelin research in the past 20 years. The story of endothelin is unique as the gene sequences of endothelin receptors and the first receptor antagonists became available within only 4 years of the identification of the peptide sequence.The first clinical study in patients with congestive heart failure was published only 3 years thereafter. Yet, despite convincing experimental evidence of a pathogenetic role for endothelin in development, cell function, and disease, many initial clinical studies on endothelin antagonism were negative. In many of these studies, study designs or patient selection were inadequate. Today, for diseases such as pulmonary hypertension, endothelin antagonist treatment has become reality in clinical medicine, and ongoing clinical studies are evaluating additional indications, such as renal disease and cancer. Twenty years after the discovery of endothelin, its inhibitors have finally arrived in the clinical arena and are now providing us with new options to treat disease and prolong the lives of patients. Possible future indications include resistant arterial hypertension, proteinuric renal disease, cancer, and connective tissue diseases.

Key words: atherosclerosis, congestive heart failure, endothelin receptor antagonists, ambrisentan, bosentan, sitaxsentan, darusentan, pulmonary hypertension, scleroderma, kidney disease, diabetic nephropathy, connective tissue disease, diabetes, metabolic syndrome, proteinuria, oncology, nephrology, cardiology, internal medicine.

Resume : Depuis son identification en tant que peptide vasoconstricteur derive de l'endothelium en 1988, l'endotheline-1, membre principal de la famille des endothelines, a suscite un immense interet dans le domaine de la science medicale et en medecine clinique, interet souligne par plus de 20 000 publications scientifiques relatives a des travaux de recherche sur les endothelines au cours des 20 dernieres annees. L'histoire de l'endotheline est unique, puisque les sequences geniques des recepteurs de l'endotheline et leurs premiers antagonistes sont devenus disponibles dans les quatre annees qui ont suivi l'identification de la sequence peptidique, et que la premiere etude clinique chez des patients atteints d'insuffisance cardiaque a ete publiee trois ans plus tard seulement. Toutefois, malgre des resultats experimentaux convaincants quant au role pathogene de l'endotheline dans le developpement, la fonction cellulaire et la maladie, de nombreuses etudes cliniques initiales sur l'antagonisme du peptide ont ete negatives. Dans plusieurs cas, le plan d'etude ou la selection des patients, ou les deux, ont ete inadequats. Aujourd'hui, l'emploi des antagonistes de l'endotheline est devenu une realite en medecine clinique pour traiter des maladies telles que l'hypertension essentielle pulmonaire, et des indications additionnelles comme la nephropathie et le cancer sont evaluees dans des etudes cliniques en cours. Vingt ans apres la decouverte de l'endotheline, ses inhibiteurs ont finalement fait leur apparition en pratique clinique et nous offrent de nouvelles possibilites pour traiter les patients et prolonger leur vie. Il est probable que les indications d'avenir comprendront aussi l'hypertension arterielle resistante, la nephropathie proteinurique, le cancer et les maladies du tissu conjonctif.

Mots-cles : atherosclerose, insuffisance cardiaque congestive, antagonistes des recepteurs de l'endotheline, ambrisentan, bosentan, sitaxsentan, darusentan, hypertension pulmonaire, sclerodermie, nephropathie, maladie du tissu conjonctif, diabete, syndrome metabolique, proteinurie, oncologie, nephrologie, cardiologie, medecine interne.

[Traduit par la Redaction]

Introduction

In the early 1980s, research efforts were concentrated on identifying new vasoactive factors following Robert Furchgott's seminal observation that endothelial cells modulate vascular tone by releasing a vasodilator factor (Furchgott and Zawadzki 1980). This factor was subsequently identified as nitric oxide (Ignarro et al. 1987), but even before that it became clear that endothelial cells also release vasoconstrictor substances (De Mey et al. 1982; Hickey et al. 1985; Rubanyi and Vanhoutte 1985; O'Brien et al. 1987). After a common effort by several groups in Japan (Masaki 1998), sequences of the gene and the peptide encoding for endothelin were published in Nature in March 1988 (Yanagisawa et al. 1988). In humans, it is now clear that endothelin represents the most potent and long-lasting vasoconstrictor known (Hillier et al. 2001; Maguire and Davenport 2002), being 100 times more potent than noradrenaline (Yanagisawa et al. 1988; Luscher and Barton 2000). Endothelins, of which endothelin-1 (ET-1) represents the predominant isoform and the biologically most relevant (Luscher and Barton 2000; Kedzierski and Yanagisawa 2001), can be considered ubiquitously expressed stress-responsive regulators working in a paracrine and autocrine fashion and having both beneficial and detrimental effects (Kedzierski and Yanagisawa 2001). Endothelins exert a number of physiological functions (Rubanyi and Polokoff 1994), including neural crest cell development and neurotransmission (reviewed in Kedzierski and Yanagisawa 2001). In the vascular system, endothelin, via activation of ETA receptors, has a basal ("tonic") vasoconstricting role and contributes to the development of vascular disease in hypertension and atherosclerosis (Schiffrin 1999; Barton 2000). Endothelins contribute to myocardial contractility (Maguire and Davenport 2002), chronotropy (Kedzierski and Yanagisawa 2001), and arrhythmogenesis (Proven et al. 2006), as well as to myocardial remodelling following congestive heart failure (Sakai et al. 1996). In the lung, the endothelin system regulates bronchial tone (Uchida et al. 1988) and the proliferation of pulmonary airway blood vessels, and thus promotes the development of pulmonary hypertension (Rubin et al. 2006). Endothelin also controls water and sodium excretion and acid-base balance in the kidney under physiologic conditions (Kohan 2006) and accelerates the development of glomerulosclerosis (Hocher et al. 1997; Remuzzi et al. 2002; Chatziantoniou and Dussaule 2005). In the brain, the endothelin system modulates cardiorespiratory centers and the release of hormones (Kedzierski and Yanagisawa 2001) and contributes to growth guidance of developing sympathetic neurons (Makita et al. 2008). In addition, endothelins affect physiology and pathophysiology of the immune system (Nett et al. 2006), liver (Berthiaume et al. 2005), muscle, bone, skin, prostate, adipose tissue (Bhattacharya and Ullrich 2006; van Harmelen et al. 2008), and reproductive tract and are involved in glucose homeostasis (Berthiaume et al. 2005; Lteif et al. 2007).

Within a remarkably short time of only 4 years after the discovery of endothelin, its receptors were cloned and receptor antagonists had become available (Arai et al. 1990; Eguchi et al. 1992). The first clinical trial in patients with congestive heart failure was performed in Zurich, Switzerland, in the early 1990s and published in 1995 (Kiowski et al. 1995). Nevertheless, it took several more years and many unsuccessful clinical trials in heart failure patients before the concept of endothelin receptor blockade could be established in clinical medicine (Remuzzi et al. 2002; Kirchengast and Luz 2005; Kirkby et al. 2008). In 2002, on the basis of convincing evidence of improved clinical status and survival in patients, bosentan (Tracleer) became the first orally active endothelin receptor antagonist to receive approval from the US Food and Drug Administration (FDA) for the treatment of patients with primary pulmonary arterial hypertension (PAH) (Channick et al. 2001; Rubin et al. 2002). Since then, several other endothelin antagonists have become available for the treatment of pulmonary hypertension, including ambrisentan (Letairis, Volibris), and sitaxsentan (Thelin).

Ongoing clinical trials are currently evaluating endothelin receptor antagonists for the treatment of resistant arterial hypertension, (Black et al. 2007), proteinuric renal disease (Barton et al. 2006; Barton 2008), cancer (Battistini et al. 2006), and autoimmune diseases such as scleroderma (Denton et al. 2006; Denton 2007; Sfikakis et al. 2007). Thus, endothelin blockade is finally being tested as a new therapeutic option in clinical medicine with the potential to improve clinical symptoms, quality of life, and survival in patients with a range of vascular and nonvascular diseases.

Endothelins and endothelin receptors

ET-1 is a 21-amino acid peptide with a hydrophobic C-terminus and 2 cysteine bridges at the N-terminus and is the main member of the endothelin peptide family (Yanagisawa and Masaki 1989). Two structurally related peptides differing by 2 and 6 amino acids, termed ET-2 and ET-3, respectively, were identified shortly after the discovery of ET-1 (Yanagisawa and Masaki 1989). ET-1 is produced by vascular endothelial and smooth muscle cells, airway epithelial cells, macrophages, fibroblasts, cardiac myocytes, brain neurons, and pancreatic islets (Ortmann et al. 2005), among others (reviewed in Luscher and Barton 2000; Kedzierski and Yanagisawa 2001). ET-2 is expressed in the ovary and by intestinal epithelial cells, and most recent studies suggest the involvement of this somewhat forgotten sibling of the endothelin family in the regulation of lung alveolarization, thermoregulation, ovulation, and intestinal epithelial cell homeostasis, and thus possibly in inflammatory bowel disease (Bramall et al. 2007; Ko et al. 2006, 2007; Chang et al. 2008). ET-3 is found in endothelial cells, brain neurons, renal tubular epithelial cells, and intestinal epithelial cells and mediates release of vasodilators, including NO and prostacyclin (Kedzierski and Yanagisawa 2001). The endothelin precursors are processed by 2 proteases to create the mature active forms (Kedzierski and Yanagisawa 2001). The 212-residue preproendothelins are cleaved at dibasic sites by furin-like endopeptidase to form biologically inactive intermediates, namely 37- to 41-amino acid peptides termed big endothelins (big ETs) or proendothelins (Fig. 1). Processing is mediated by a family of membranebound zinc metalloproteases, from the neprilysin superfamily, termed endothelin-converting enzymes (ECEs) (reviewed in Kedzierski and Yanagisawa 2001). In addition to these proteases, other enzymes (Guo and Rabinovitch 1998), such as non-ECE metalloproteinase (Ikeda et al. 1999), must contribute to the final processing step, since in mice lacking both ECE-1 and ECE-2 the levels of mature endothelin peptides are reduced by only one-third (Yanagisawa et al. 2000). Recent experimental evidence suggests that carboxypeptidase A (cathepsin A) plays an important role in degradation of the ECE product ET-1 (Seyrantepe et al. 2008).

[FIGURE 1 OMITTED]

Two 7-transmembrane domain, G protein-coupled endothelin receptors ([ET.sub.A] and [ET.sub.B]) have been identified in humans (Davenport 2002). It is currently not clear whether receptor dimerization into homo- or heterodimers (Evans and Walker 2007) plays a role in endothelin receptor activity and function in vivo, such as the effect of endothelin on diuresis (Kohan 2006), nor is it clear whether receptor dimerization is affected by drug treatment. The [ET.sub.A] receptor shows subnanomolar affinities for ET-1 and ET-2 and 100-fold lower affinity for ET-3 (Kedzierski and Yanagisawa 2001). [ET.sub.B] has equal subnanomolar affinities for all endothelin peptides. The ETA receptor can be considered the primary vasoconstrictor and growth-promoting receptor, whereas the [ET.sub.B] receptor inhibits cell growth and vasoconstriction in the vascular system and also functions as a "clearance receptor," as evidenced by the fact that selective ETB blockade inhibits the accumulation of intravenously administered radiolabeled ET-1 in tissue (Luscher and Barton 2000; Kedzierski and Yanagisawa 2001). This ETB receptor-mediated clearance mechanism is particularly important in the lung, which clears about 80% of circulating ET-1 (Luscher and Barton 2000).

Hypertension and vascular disease

The identification of endothelin as a vasoconstrictor (Yanagisawa et al. 1988) and the discovery of its release from vascular endothelial cells suggested that this peptide was involved in the pathogenesis of hypertension and vascular disease (Iwasa et al. …

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