Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Endothelin-1 is an endothelium-derived compound that exerts a variety of hemodynamic and structural alterations in the cardiovascular and pulmonary circuits. The endothelin system is activated in an assortment of disorders and disease states, such as systemic hypertension, pulmonary hypertension, atherosclerosis, acute coronary syndromes, and congestive heart failure. The actions of endothelin are mediated by two types of receptors: ETA and ETB, which are widely distributed in the cardiovascular system. The complexity of biophysical effects mediated by these two types of receptors dictates the therapeutic implications, that is, selective (ETA) versus dual (ETA/ ETB) receptor antagonism. Preliminary experimental and clinical studies reveal a role played by endothelin as a pathogenetic substance and, conversely, a possible role for endothelin antagonism in clinical medicine.
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PMID:Possible therapeutic role of endothelin antagonists in cardiovascular disease. 1462 76

Endothelins are a family of three peptides of 21 amino acids with strong vasoconstrictor effects. The three peptides are encoded by three different genes and derived from precursors (" big endothelins") which are cleaved by metalloproteases, named endothelin-converting enzyme. Two receptors have been cloned, ET-A and ET-B which bind the three endothelins with various affinities. The diverse expression pattern of the endothelin system (ET) components is associated with a complex pharmacology and its counteracting physiological actions. New modulators of the ET system have been described : retinoic acid, leptin, prostaglandins, hypoxia. Endothelins can be considered as regulators working in paracrine and autocrine fashion in a variety of organs in different cellular types. The ET system has beneficial and detrimental roles in mammals. The different components have been shown to be essential for a normal embryonic and neonatal development, for renal homeostasis and maintenance of basal vascular tone. They are involved in physiological and tumoral angiogenesis. They affect the physiology and pathophysiology of the liver, muscle, skin, adipose tissue and reproductive tract. The endothelin system participates in the development of atherosclerosis as well as pulmonary hypertension, and mediates cardiac remodeling in heart failure. Elaboration of new animal models (knock-out, pathophysiological models em leader ) will allow the clear genetic dissection of physiological and pathophysiological roles of the endothelin system.
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PMID:[What is the role of endothelin system?]. 1506 80

Two types of lead structures for selective agonists of ETA, a biological target not yet fully elucidated, has first been discovered via diversity-guided pharmacophore simplification and simulation. And it is first demonstrated that potent selective ETA agonists might be useful for protection of endothelium and for prophylaxis and treatment of cardiovascular diseases with endothelial dysfunction such as atherosclerosis and thrombosis.
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PMID:Discovering selective agonists of endothelial target for acetylcholine (ETA) via diversity-guided pharmacophore simplification and simulation. 1514 37

Endothelins (ETs) are potent vasoconstrictor peptides and are associated with several disease states like pulmonary hypertension, systemic hypertension and heart failure. Endothelin-1 (ET-1) is the first member of the family and it has the receptor subtypes known as ETA and ETB. The receptors ETA and ETB are attractive new therapeutic targets for diseases associated with elevated ET-1 levels. Several studies have thus led to the discovery of selective ETA receptor antagonists as well as non-selective ETA/ETB antagonists. The preclinical and clinical studies have clearly established that these antagonists are effective in the treatment of essential hypertension, pulmonary hypertension, heart failure and atherosclerosis. The advances in this area have resulted in the FDA approval of the orally active dual antagonist Bosentan for pulmonary hypertension in 2001. This review highlights the synthesis and structure-activity of the endothelin receptor antagonists and covers the literature in this area up to 2001.
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PMID:Endothelin receptor antagonists: an overview of their synthesis and structure-activity relationship. 1585 28

In humans, the endothelins (ETs) comprise a family of three 21-amino-acid peptides, ET-1, ET-2 and ET-3. ET-1 is synthesised from a biologically inactive precursor, Big ET-1, by an unusual hydrolysis of the Trp21 -Val22 bond by the endothelin converting enzyme (ECE-1). In humans, there are four isoforms (ECE-1a-d) derived from a single gene by the action of alternative promoters. Structurally, they differ only in the amino acid sequence of the extreme N-terminus. A second enzyme, ECE-2, also exists as four isoforms and differs from ECE-1 in requiring an acidic pH for optimal activity. Human chymase can also cleave Big ET-1 to ET-1, which is cleaved, in turn, to the mature peptide as an alternative pathway. ET-1 is the principal isoform in the human cardiovascular system and remains one of the most potent constrictors of human vessels discovered. ET-1 is unusual in being released from a dual secretory pathway. The peptide is continuously released from vascular endothelial cells by the constitutive pathway, producing intense constriction of the underlying smooth muscle and contributing to the maintenance of endogenous vascular tone. ET-1 is also released from endothelial cell-specific storage granules (Weibel-Palade bodies) in response to external stimuli. ETs mediate their action by activating two G protein-coupled receptor sub-types, ETA and ET(B). Two therapeutic strategies have emerged to oppose the actions of ET-1, namely inhibition of the synthetic enzyme by combined ECE/neutral endopeptidase inhibitors such as SLV306, and receptor antagonists such as bosentan. The ET system is up-regulated in atherosclerosis, and ET antagonists may be of benefit in reducing blood pressure in essential hypertension. Bosentan, the first ET antagonist approved for clinical use, represents a significant new therapeutic strategy in the treatment of pulmonary arterial hypertension (PAH).
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PMID:Endothelin. 1699 23

Hypercholesterolemia (HC) may trigger early renal injury, partly by impairing the function or the structure of renal microvessels (MV). The endothelin (ET) system is upregulated in HC and can have an impact on the renal microcirculation by regulating MV tone, growth factors, and remodeling. It was hypothesized that ET-A blockade would protect the HC kidney by improving the function and attenuating the damage of intrarenal MV. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 wk of experimental HC, HC and chronic supplementation with the ET receptor A blocker ABT-627 (HC+ET-A, 0.75 mg/kg per d), and normal controls. Renal MV architecture then was studied ex vivo using three-dimensional microcomputed tomography imaging, and growth factors and remodeling pathways were explored in renal tissue. The HC kidney showed increased MV density compared with normal (77.68 +/- 5.1 versus 62.9 +/- 4.8 vessels/cm(2); P = 0.04) but blunted endothelial function. Chronic ET-A blockade in HC upregulated renal vascular growth factors, further increased renal MV density (139.9 +/- 8.4 vessels/cm(2); P = 0.001 versus normal and HC), and decreased renal tissue and MV remodeling. Furthermore, ET-A blockade in HC decreased MV tortuosity and improved MV endothelial function, suggesting accelerated stabilization and maturation of neo-vessels. Modulation of renal MV architecture and function in HC is mediated partly by the endogenous ET system. Notably, ET-A blockade enhanced the proliferation and facilitated the maturation of renal MV in the HC kidney and improved renal MV remodeling and function. This study suggests novel renoprotective effects of ET-A blockers and supports further exploration of strategies that target the ET pathway in HC and atherosclerosis.
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PMID:Endothelin-a receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia. 1708 39

Endothelin-1 (ET-1), a vasoactive peptide, is believed to contribute to the pathogenesis of vascular abnormalities such as hypertension, atherosclerosis, hypertrophy and restenosis. ET-1 elicits its biological effects through the activation of two receptor subtypes, ET-A and ET-B that belong to a large family of transmembrane guanine nucleotide-binding protein-coupled receptors (GPCRs). ET-1 receptor activation results in the stimulation of several signaling pathways including mitogen-activated protein kinases (MAPKs), phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB). An intermediary role of Ca(2+)/calmodulin-dependent protein kinases (CaMK), protein kinase C (PKC) as well as receptor and non-receptor protein tyrosine kinases in triggering the activation of MAPK and PI3-K/PKB signaling in response to ET-1 has been suggested. Activation of these pathways by ET-1 is intimately linked with the regulation of cellular hypertrophy, growth, proliferation and cell survival. Here we provide an overview of these signaling pathways in vascular smooth muscle cells (VSMCs) with an emphasis on their potential role in vascular pathophysiology.
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PMID:Endothelin-1-induced signaling pathways in vascular smooth muscle cells. 1726 12

Endothelin 1 mediates coronary vasoconstriction and endothelial dysfunction via endothelin receptor type A (ET(A)) activation. However, the effects of selective endothelin receptor type B (ET(B)) and combined ET(A+B) receptor blockade on coronary vasomotion are unknown. We measured coronary vascular tone and endothelium-dependent and -independent vasomotor function before and after selective infusion of BQ-788 (an ET(B) receptor antagonist) or combined infusion of BQ-788+BQ-123 (an ET(A) antagonist) into unobstructed coronary arteries of 39 patients with coronary atherosclerosis or risk factors undergoing cardiac catheterization. BQ-788 did not affect epicardial diameter but constricted the microcirculation (P<0.0001), increased coronary sinus endothelin, and reduced nitrogen oxide levels. In contrast, BQ-123+BQ-788 dilated epicardial (P<0.0001) and resistance (P=0.022) arteries. Responses to acetylcholine and sodium nitroprusside were unaffected by BQ-788 alone. Epicardial endothelial dysfunction improved after BQ-123+BQ-788 (P=0.007). Coronary microvascular responses to acetylcholine and sodium nitroprusside were unaffected by BQ-123+BQ-788. We conclude that selective ET(B) receptor antagonism causes coronary microvascular constriction, without affecting epicardial tone or endothelial function, via reduced endothelin clearance and NO availability. Combined ET(A+B) blockade dilates coronary conduit and resistance vessels and improves endothelial dysfunction of the epicardial coronary arteries. Thus, endogenous endothelin, predominantly via ET(A) receptor stimulation, contributes to basal constrictor tone and endothelial dysfunction, whereas ET(B) activation mediates vasodilation in human coronaries. Our data suggest that selective ET(A) blockade may have greater therapeutic potential than nonselective agents, particularly for treatment of endothelial dysfunction in atherosclerosis.
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PMID:Endogenous endothelin in human coronary vascular function: differential contribution of endothelin receptor types A and B. 1735 14

Endothelin (ET)-1 receptor blockade improves endothelial function in the forearm of patients with atherosclerosis. The aim was to investigate whether intracoronary ET receptor blockade improves coronary endothelial function and increases blood flow in patients with coronary artery disease. Ten patients received a 60-minute infusion of either the selective ETA receptor antagonist BQ123 (40 nmol/min, n = 6) or BQ123 + the ETB receptor antagonist BQ788 (40 nmol/min, n = 4). In all patients, substance P, an endothelium-dependent vasodilator, did not increase baseline coronary flow reserve with thermodilution (CFRThermo) (0.71 +/- 0.14 s during NaCl versus 0.59 +/- 0.14 s during substance P) or baseline quantitative coronary angiography (QCA) (2.74 +/- 0.16 mm versus 2.83 +/- 0.20 mm). After ET receptor blockade, however, the response to substance P was significantly improved as determined both by CFRThermo (0.62 +/- 0.14 s during NaCl versus 0.48 +/- 0.10 s during substance P, p < 0.05) and by QCA (2.70 +/- 0.18 mm versus 2.85 +/- 0.19 mm, p < 0.05). In addition, ET blockade increased blood flow in all patients by 16% +/- 10% (n = 10, p < 0.05) and in the BQ123 group by 22% +/- 16% (n = 6, p < 0.05). Furthermore, ETA blockade increased blood flow significantly more than did dual ETA/ETB blockade (p < 0.05). These findings indicate that ET receptor blockade may be a new therapeutic strategy to improve coronary vascular function in patients with coronary artery disease.
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PMID:Intracoronary endothelin receptor blockade improves endothelial function in patients with coronary artery disease. 1901 69

Endothelin (ET) was first isolated and described by Yanagisawa et al. and has since been described as one of the most potent known vasoconstrictor compounds. ET-1 mediates its effects via two types of receptors, ETA and ETB, which are expressed in the vascular smooth muscle cells, endothelial cells, intestines and brain. Secretion of ET-1 results in long-lasting vasoconstriction, increased blood pressure and, in turn, overproduction of free radicals. As dysregulation of the endothelin system is an important factor in the pathogenesis of several diseases including atherosclerosis, hypertension and endotoxic shock, the ETA and ETB receptors are attractive therapeutic targets for treatment of these disorders. The biosynthesis and release of ET-1 are regulated at the transcriptional level. Studies have shown that p38MAP kinase, nuclear factor kappaB (NF-kappaB), PKC/ERK and JNK/c-Jun all take part in the ROS-activated production of ET-1. Furthermore, administration of ET(A) significantly reduces the generation of free radicals. However, treatment with ETB receptor blockers does not elicit the same effect. Therefore, the effects of endothelin receptor blockers on blood pressure and the generation of free radicals remain debatable. This review summarizes recent investigations into the role of endothelin receptor blockers with respect to the modulation of hemodynamic parameters and the generation of free radicals.
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PMID:Role of endothelin-1 receptor blockers on hemodynamic parameters and oxidative stress. 2036 Jun 13


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