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)

Urotensin-II (U-II), a peptide isolated from the urophysis of teleost fish 35 years ago, is the endogenous ligand of the mammalian orphan receptor GPR14/SENR. Recently, human homologues of both the receptor (UT-II) and the peptide (hU-II) have been discovered. Following de-orphanization, hU-II was declared the 'new endothelin' as initial studies suggested similarities between the peptides, and in isolated arteries of cynomolgus monkey U-II was a more potent constrictor than endothelin-1 (ET-1), with equal efficacy. However, effects of U-II in vascular tissue from other mammalian species are variable and although potent, U-II exhibits a lesser maximal response than ET-1. In contrast, in humans U-II has emerged as a ubiquitious constrictor of both arteries and veins in vitro and elicits a reduction in blood flow in the forearm and skin microcirculation in vivo. In addition to direct vasoconstrictor activity on smooth muscle receptors, endothelium-dependent U-II-mediated vasodilatation has also been observed. Non-vascular, peripheral actions of U-II include potent inotropy and airway smooth muscle constriction and U-II and its receptor are present throughout rat brain implying a possible neurotransmitter or neuromodulatory role in the central nervous system. U-II is proposed to contribute to human diseases including atherosclerosis, cardiac hypertrophy, pulmonary hypertension and tumour growth. The development of selective receptor antagonists should help to clarify the relative importance of hU-II as a multifunctional peptide in mammalian systems and its role in disease. What is clear is that U-II is emerging as a new and potentially important mammalian transmitter.
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PMID:Is urotensin-II the new endothelin? 1238 71

The endothelins (ET) are among the most potent vasoconstrictors identified to date, and have been implicated in such diseases as renal failure, pulmonary hypertension, atherosclerosis, and congestive heart failure. There is currently interest in developing selective antagonists of the ET-A subtype receptor, and one such antagonist is SB-247083 ((E)-[1-butyl-5-[2-(2-carboxyphenyl) methoxy-4-chlorophenyl]-1H-pyrazole-4-yl]-2-[5-methoxydihydrobenzofuran-6-yl]methyl]-2-propionic acid). This investigation was conducted to evaluate the preclinical pharmacokinetics of SB-247083. Clearance of SB-247083 was low to moderate in the rat and monkey, and high in the dog. Oral bioavailability of SB-247083 administered as a solid formulation of the free acid was 24% in the rat, but low in the dog (4%) and the monkey (2%). An extensive in vitro salt form and formulation screen resulted in the identification of a formulation containing the monoarginyl salt with improved dissolution properties. This formulation provided a 2- to 4-fold increase in oral bioavailability in each of the preclinical species. In the dog, this improvement was reversed by the pre-administration of 0.1 N HCl to normalize the achlorhydric fasting dog stomach. These data show that SB-247083 may have suitable drug properties for progression in development.
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PMID:Pharmacokinetics of SB-247083, a potent and selective endothelin(A) receptor antagonist, in the rat, dog, and monkey. 1241 74

Clinical trials have established bosentan, an orally active non-selective endothelin (ET) receptor antagonist, as a beneficial treatment in pulmonary hypertension. Trials have also shown short-term benefits of bosentan in systemic hypertension and congestive heart failure. However, bosentan also increased plasma levels of ET-1, probably by inhibiting the clearance of ET-1 by endothelin type B (ET(B)) receptors, and this may mean its effectiveness is reduced with long-term clinical use. Preliminary data suggests that selective endothelin type A (ET(A)) receptor antagonists (BQ-123, sitaxsentan) may be more beneficial than the non-selective ET receptor antagonists in heart failure, especially when the failure is associated with pulmonary hypertension. Experimental evidence in animal disease models suggests that non-selective ET or selective ET(A) receptor antagonism may have a role in the treatment of atherosclerosis, restenosis, myocarditis, shock and portal hypertension. In animal models of myocardial infarction and/or reperfusion injury, non-selective ET or selective ET(A) receptor antagonists have beneficial or detrimental effects depending on the conditions and agents used. Thus clinical trials of the non-selective ET or selective ET(A) receptor antagonists in these conditions are not presently warranted. Several selective endothelin-converting enzyme inhibitors have been synthesised recently, and these are only beginning to be tested in animal models of cardiovascular disease, and thus the clinical potential of these inhibitors is still to be defined.
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PMID:The therapeutic potential of endothelin-1 receptor antagonists and endothelin-converting enzyme inhibitors on the cardiovascular system. 1243 1

Three isopeptides of endothelin (ET-1, -2, and -3) exert various actions through stimulation of two sub-types of receptor (ETA and ETB). Vascular endothelial cells produce only ET-1. In addition to its powerful vasoconstrictor action, ET-1 has direct mitogenic actions on cardiovascular tissues, as well as comitogennic actions with a wide variety of growth factors and vasoactive substances. ET-1 also promotes the synthesis and secretion of growth factors and various substances, including extracellular constituents. These effects of endogenous ET-1 would naturally be thought to be concerned with the development and/or aggravation of chronic cardiovascular diseases; e.g., hypertension, pulmonary hypertension, vascular remodeling (stenosis, atherosclerosis), renal failure, and heart failure. A large number of peptide and orally active non-peptide endothelin receptor antagonists have been developed, and utilized to analyze physiological and pathophysiological roles of endogenous ET-1. These antagonists have been shown to exert excellent therapeutic effects in animal models of various kinds of diseases by either acute or chronic treatment. Therapeutic treatment of patients suffering from the above-mentioned cardiovascular diseases with ET-receptor antagonists have also been taking place, and bosentan (ETA/ETB antagonist) was recently approved by the FDA as a formal therapeutic drug for pulmonary hypertension. In this review, perspectives for therapeutic applicability of ET-receptor antagonists will be explored.
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PMID:[New expansion of endothelin research: perspectives for clinical application of endothelin-receptor antagonists]. 1261 54

Obstructive sleep apnea (OSA) is a common disorder associated with an increased risk of cardiovascular disease and stroke. As it is strongly associated with known cardiovascular risk factors, including obesity, insulin resistance, and dyslipidemia, OSA is an independent risk factor for hypertension and has also been implicated in the pathogenesis of congestive cardiac failure, pulmonary hypertension, arrhythmias, and atherosclerosis. Obesity is strongly linked to an increased risk of OSA, and weight loss can reduce the severity of OSA. The current standard treatment for OSA-nasal continuous positive airway pressure (CPAP)-eliminates apnea and the ensuing acute hemodynamic changes during sleep. Long-term CPAP treatment studies have shown a reduction in nocturnal cardiac ischemic episodes and improvements in daytime blood pressure levels and left ventricular function. Despite the availability of effective therapy, OSA remains an underdiagnosed and undertreated condition. A lack of physician awareness is one of the primary reasons for this deficit in diagnosis and treatment.
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PMID:Obstructive sleep apnea and cardiovascular disease. 1274 77

Endothelin-1 (ET-1) is a pleiotropic hormone produced primarily by the endothelium. Synthesis of ET-1 is stimulated by the major signals of cardiovascular stress, such as vasoactive agents (angiotensin II, norepinephrine, vasopressin, and bradykinin), cytokines (e.g., tumor necrosis factor alpha and transforming growth factor beta), and other factors, including thrombin and mechanical stress. ET-1 induces vasoconstriction, is proinflammatory, promotes fibrosis, and has mitogenic potential, important factors in the regulation of vascular tone, arterial remodeling, and vascular injury. These effects are mediated via two receptor types, ETA and ETB. The role ET-1 plays in normal cardiovascular homeostasis and in mild essential hypertension in humans is unclear. However, certain groups of essential hypertensive patients may have ET-1-dependent hypertension, including blacks (subjects of African descent), salt-sensitive hypertensives, patients with low renin hypertension, and those with obesity and insulin resistance. ET-1 has also been implicated in severe hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all of these conditions, plasma immunoreactive ET levels are elevated and tissue ET-1 expression is increased. Accordingly, it is becoming increasingly apparent that ET-1 plays an important role in cardiovascular disease and in some forms of hypertension in humans. Data from clinical trials using combined ETA-ETB receptor blockers have already demonstrated significant blood-pressure-lowering effects. Thus, targeting the endothelin system may have important therapeutic potential in the treatment of hypertension, particularly by contributing to the prevention of target organ damage and the management of cardiovascular disease.
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PMID:Role of endothelin in human hypertension. 1283 65

Atherosclerosis is a major risk factor for both myocardial infarction and stroke. A key aspect of this disease is the imbalance of vasoactive factors. In this concise review, we focus on the role of endothelin-1 in the atherosclerotic process and other vasculopathies. Previously, we have demonstrated that there is a correlation between the expression of endothelin and the underlying atherosclerotic lesion. Immunoreactivity was observed for both ET-1 and ECE-1 in endothelial cells, smooth muscle cells, and macrophages within lesions. Endothelin's role in atherosclerosis must extend from its varying physiological activities, including vasoconstriction, mitogenesis, neutrophil adhesion, and platelet aggregation, and hypertrophy, as well as its propensity to induce the formation of reactive oxygen species. We also discuss regulation of endothelin by angiotensin II, reactive oxygen species, thrombin, aging, and LDL in the cardiovascular system. Finally, we demonstrate the role of endothelin in pulmonary hypertension and transplant associated vasculopathy.
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PMID:Endothelin-1 in atherosclerosis and other vasculopathies. 1283 69

The Committee reviewed cardiac involvement in the antiphospholipid antibody syndrome. The Committee's recommendations are: Valve abnormalities: anticoagulation is recommended for symptomatic patients with valvulopathy. Prophylactic antiplatelet therapy may be appropriate for asymptomatic patients (recommended by 13/17 experts in an independent review). Committee members disagreed whether corticosteroid therapy is helpful, but agree that distinguishing among presumptive valvulitis (valve thickening on echocardiogram), valve deformity and vegetations is important, as treatment implications may differ. Occlusive arterial disease (angina, myocardial infarction): the Committee recommends aggressive treatment of all risk factors for atherosclerosis (hypertension, hypercholesterolaemia, smoking) and liberal use of folic acid, B vitamins and cholesterol-lowering drugs (preferably statins). Hydroxychloroquine for cardiac protection in APS patients may be considered. The Committee also recommends warfarin anticoagulation for those who have suffered thrombosis in the absence of atherosclerosis, but recognizes that developing data may support the use of antiplatelet agents instead. Intracardiac thrombi: the Committee recommends intensive warfarin anticoagulation, and consultation with cardiac surgeons when appropriate. Ventricular dysfunction: the Committee has no recommendations on this aspect of cardiac disease. Pulmonary hypertension: the Committee recommends intensive anticoagulation with warfarin and clinical trials of bosentan, epoprostenol and other new agents.
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PMID:Cardiac disease in the antiphospholipid syndrome: recommendations for treatment. Committee consensus report. 1289 91

Endothelin-1 (ET-1) is a potent vasoconstrictor and growth-promoting mediator that is involved in the maintenance of vascular tone within the healthy circulation. However, a pathogenic role has been implicated by its overproduction in a number of cardiovascular diseases, which include pulmonary hypertension, congestive heart failure, atherosclerosis, and coronary vasospasm. ET-1 mRNA expression and peptide production in human vascular smooth muscle cells (HVSMCs) are markedly increased by exposure to tumor necrosis factor-alpha and interferon-gamma. The intracellular signaling mechanism involved in this pathway is not known. Because the transcription factors nuclear factor-kappaB (NF-kappaB), signal transducer and activator of transcription 1 (STAT1), and interferon regulatory factor-1 (IRF-1) often mediate the effects of cytokines in target cells the aim of this study was to determine whether the production of ET-1 after exposure of HVSMCs to cytokines depends upon synergism between NF-kappaB and STAT1/IRF-1. Immunoblotting showed that cytokine-stimulation of ET-1 release in VSMCs involves nuclear translocation of NF-kappaB and STAT1. Cytokines also induced an increase in IRF-1 protein expression. Antisense oligonucleotides to NF-kappaB, STAT1, and IRF-1 significantly inhibited cytokine induced ET-1 release. In conclusion, NF-kappaB, STAT1, and IRF-1 activation are involved in the stimulation by cytokines of ET-1 release from HVSMCs. However, nuclear run-on assays would provide definitive proof that ET-1 is regulated transcriptionally by cytokines. Because up-regulated production of ET-1 within VSMCs may underlie the causative role of ET-1 in a number of disease states, this finding indicates that NF-kappaB, STAT1, and IRF-1 within HVSMCs could be central to a number of vascular pathologies and that inhibition of this pathway could be of therapeutic benefit.
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PMID:Role for nuclear factor-kappaB and signal transducer and activator of transcription 1/interferon regulatory factor-1 in cytokine-induced endothelin-1 release in human vascular smooth muscle cells. 1450 Jul 49

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


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