Endothelin-1

Endothelin-1, a peptide initially purified from porcine aortic endothelial cells, has been shown to be expressed by human pneumocytes type II in lung fibrosis (Giaid et al. 1993), by rat pneumocytes II (Crestani et al. 1994), and a cell line derived from rat pneumocytes II (L2 Markevitz et al. 1995). ET-1 has potent vascular and bronchial smooth muscle cell constrictor properties, acts as a mitogen for different cell types, such as fibroblasts or smooth muscle cells (Battistini et al. 1993), and is involved in the modulation of the inflammatory response through a direct effect on alveolar macrophages (Na-GASE et al. 1990) or mast cells (Ehrenreich et al. 1992). ET-1 production is inhibited by IL-ip (Odoux et al. 1997). IL-ip effect was dependent on protein synthesis, was partially prevented by indomethacin, and was totally prevented by dexamethasone. 

The powerful vasoconstrictive and mitogenic activity of endothelin 1 (ET-1) makes generation of an ET-1 antagonist a key target for possible therapeutic intervention. Two receptor subtypes, ET and ETb, bind ET-1 and other closely related peptides (ET-2 and ET-3). The ET receptor mediates vaso- 

Researchers at SmithKline Beecham pharmaceuticals began their quest for a nonpeptide ET antagonist by screening compounds that contained features of ET-1 known to be important to receptor binding. 

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Endothall [45-73-2] Endothelins Endothia parasitica Endothion [2778-04-3] Endotoxin... 

Nontraditional Hormones. Novel hormones identified ia cardiovascular tissue have profound effects on maintenance of blood pressure and blood volume ia mammals. Atrial natriuretic hormone (ANH) is a polypeptide hormone secreted from the atria of the heart. When the cardiac atrium is stretched by increased blood volume, secretion of ANH is stimulated ANH ia turn increases salt and water excretion and reduces blood pressure (6). Endothelin is a polypeptide hormone secreted by endothehal cells throughout the vasculature. Although endothelin is released into the circulation, it acts locally in a paracrine fashion to constrict adjacent vascular smooth muscle and increase blood pressure (7). 

Endothelin. The endothelin (ET) peptide family (50) comprises thiee peptides ET-1 (133), ET-2 (134), and ET-3 (135). ET-1, the most abundant, is a 21-amino acid peptide. A 203-amino acid peptide piecuisoi, piepioET, is cleaved after translation by endopeptidases to form a 38-amino acid proET which is converted to active ET by a putative endothelin-converting enzyme (ECE). ET-3 differs from ET-1 and ET-2 by sis amino acids. 

Ro 46-2005 (140) and SB 209670 (141) are the first synthetic orally active endothelin receptor antagonists. The ET receptor is a third ET receptor. 

Biological function and chemistry of endothelin, vasoactive peptide with macro-cyclic fragments formed by disulfide bridges between cysteine residues 99CCC1211. 

Ca2+ channel Dopamine Dj Endothelin ETa Endothelin ETb Histamine H2 Muscarinic ml Muscarinic m2 Muscarinic m3 Muscarinic m4 NE transporter Nicotinic Ach NPY,... 

Protein Trafficking and Quality Control Intracellular Transport Palmitoylation Endothelins... 

Chymase (mast cell protease type II), a chymotrypsin-like protease, is a serine protease found in mucosal mast cells, which catalyzes the conversion of angiotensin I to angiotensin II and of big endothelin 1 (ET1) to ET1 (1-31). 

Endothelin Concerting Enzymes (ECEs) belong to the family of metalloproteases that catalyze the proteolytic activation of big endothelins. 

Endothelins comprise a family of three vasoactive isopeptides of 21 amino acids that have an essential role in the regulation of the vascular and bronchiolar tone and the control of natriuresis in the kidney. Endothelin peptides are also involved in nociception and have a critical role in the progression of prostate and ovarian cancer. 

In 1985, a peptide was described in the supernatants of endothelial cells that mediated vasoconstriction [1]. This peptide was isolated and sequenced, and the cDNA was cloned. According to its origin from endothelial cells it was named endothelin. 

Endothelins. Table 2 Properties of the different isoforms of endothelin-converting enzymes... 

The ECE isoforms show different subcellular distributions and enzymatic characteristics (Table 2). ECE-la and ECE-lc are mainly expressed at the cell surface, whereas ECE-lb, ECE-Id and ECE-2 are expressed intracellularly. Plasma membrane-bound ECE cleaves big-ET-1 circulating in the blood, whereas intracellular ECE isoforms are involved in the generation of mature endothelins. In addition, ECEs (as well as NEP and the insulin-degrading enzyme) contribute to the degradation of amyloid (3 (A 3) peptide. 

The endothelin receptor subtypes show differences in their signal transduction, ligand binding and tissue distribution. The ETA receptor is isopeptide-selective and binds ET-1 and ET-2 with the same and ET-3 with 70-100-fold lower affinity. The ETB receptor binds all three isoforms with the same affinity. 

ET-1 also stimulates anti-apoptotic signal cascades in fibroblasts, vascular smooth muscles and endothelial cells (via phosphatidylinositol-3-kinase and Akt/pro-tein kinase B). In prostate and ovarian cancer, upregulation of endothelin synthesis and ETA receptors has been associated with a progression of the disease. The inhibiton of ETA receptors results in a reduced tumour growth. In malignant melanoma, ETB receptors are associated with tumour progression. Endothelins can also stimulate apoptosis in stretch-activated vessels via the ETB receptor, which contrasts the above-mentioned effects. The molecular basis for these differential anti- and pro-apoptotic reactions mediated by endothelins remains elusive. 

Sites of endothelin-receptor expression. ETA receptors are expressed in the smooth muscle cells of the vascular medial layer and the airways, in cardiac myocytes, lung parenchyma, bronchiolar epithelial cells and prostate epithelial cells. ETB receptors are expressed in endothelial cells, in bronchiolar smooth muscle cells, vascular smooth muscle cells of certain vessels (e.g. saphenous vein, internal mammary artety), in the renal proximal and distal tubule, the renal collecting duct and in the cells of the atrioventricular conducting system. 

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