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)

Endothelins build a peptide family composed of three isoforms, each of them containing 21 amino acids. Endothelin-1 is the isoform mainly responsible for any cardiovascular action and therefore the sole scope of this review. Endothelin-1 is the most potent endogenous vasoconstrictor known; in addition it acts as a potent (co)mitogen. There is a substantial body of experimental evidence that endothelin-1 may contribute not only to sustained vasoconstriction, but also to remodeling within the cardiovascular system. Thus, with the help of endothelin receptor antagonists (available for a few years) the involvement of mainly ETA receptors in structural diseases such as heart failure, pulmonary hypertension, atherosclerosis, restenosis, systemic hypertension, and chronic renal failure has been shown. These data make endothelin receptor antagonists, and especially those selective for the ETA receptor, promising agents for the treatment of chronic cardiovascular diseases associated with remodeling. Currently several chemically distinct, orally available members of this novel class of therapeutic agents are under clinical investigation.
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PMID:Endothelin-1 and endothelin receptor antagonists in cardiovascular remodeling. 1046 Jun 93

Recent studies of intravascular ultrasound of the pulmonary arteries suggest that the technique can detect intimal and medial thickening in patients with pulmonary hypertension, potentially providing a method of assessing severity of pulmonary vascular disease in life. A major drawback of the technique is that only the elastic pulmonary arteries are accessible to current ultrasound catheters. The aim of this study was to determine whether morphological changes in vessels accessible to intravascular imaging reflect severity of pulmonary vascular disease and are of a sufficient degree to be detectable by current ultrasound catheters. Morphometric studies of the elastic pulmonary arteries were performed in specimens of lungs from 24 patients who had died with pulmonary hypertension (aged 3 weeks-9 years) and compared with measurements from infants who had died from sudden infant death syndrome. Morphological changes evident in the elastic pulmonary arteries in pulmonary hypertension included luminal dilation and medial thickening but these changes were too variable to be predictive of the severity of peripheral pulmonary vascular disease. Intimal thickening and atherosclerosis were present only in those with advanced pulmonary hypertensive disease. The changes of medial thickening and luminal dilation, nonetheless, are too variable to be predictive of the severity of peripheral pulmonary vascular disease. Thus, imaging by intravascular ultrasound may help confirm advanced pulmonary vascular disease, but is unlikely to differentiate less severe pulmonary vascular disease when the patient may still potentially be operable.
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PMID:Morphology of the elastic pulmonary arteries in pulmonary hypertension: a quantitative study. 1047 25

Intimal hyperplasia is the process by which the cell population increases within the innermost layer of the arterial wall, such as occurs physiologically during closure of the ductus arteriosus and during involution of the uterus. It also occurs pathologically in pulmonary hypertension, atherosclerosis, after angioplasty, in transplanted organs, and in vein grafts. The underlying causes of intimal hyperplasia are migration and proliferation of vascular smooth muscle cells provoked by injury, inflammation, and stretch. This review discusses, at a molecular level, both the final common pathways leading to smooth muscle migration and proliferation and their (patho)-physiological triggers. It emphasizes the key roles played by growth factors and extracellular matrix-degrading metalloproteinases, which act in concert to remodel the extracellular matrix and permit cell migration and proliferation.
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PMID:Molecular mechanisms in intimal hyperplasia. 1068 64

Endothelin (ET) -1 is a potent vasoconstrictor and promitogenic peptide produced by the vascular endothelium. The ET system is activated in atherosclerosis and in most cardiovascular conditions associated with increased vascular tone and remodelling. There are two ET-receptor (ET-R) subtypes: the ETA-Rs mediate smooth muscle vasoconstriction and proliferation, and the more complex ETB-Rs have antagonistic actions - they serve a dual role of clearance and vasodilation in the endothelium, while in smooth muscle cells they also provoke vasoconstriction. Selective ETA-R and nonselective ETA/B-R antagonists are entering the clinical development phase. These agents have shown their effectiveness in the therapy of various models of heart failure, pulmonary hypertension, systemic hypertension and ischemia-reperfusion and in the prevention of restenosis. In patients with congestive heart failure, short term ET-antagonist (ET-R) therapy provides hemodynamic and symptomatic improvement. Because of the dual role of the ETB-R, nonselective antagonists may provide greater or fewer benefits than selective ETA-R antagonists: a lack of direct comparison of the two categories of agents, however, does not allow this distinction at present. In the evaluation of this new class of therapeutic agents, particular attention should be paid to potency and receptor selectivity of a compound, the alterations in ETA-R and ETB-R activity brought on by pathological conditions, the proportions of ETA versus ETB-R of the target system, and finally, the net importance of the possible protective role of the endothelial ETB versus the deleterious effects of the smooth muscle ETB-R.
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PMID:Endothelin receptor antagonists and their developing role in cardiovascular therapeutics. 1093 9

The 21-amino acid peptide endothelin-1 (ET-1) is the predominant isoform of the endothelin peptide family, which includes ET-2, ET-3, and ET-4. It exerts various biological effects, including vasoconstriction and the stimulation of cell proliferation in tissues both within and outside of the cardiovascular system. ET-1 is synthesized by endothelin-converting enzymes (ECE), chymases, and non-ECE metalloproteases; it is regulated in an autocrine fashion in vascular and nonvascular cells. ET-1 acts through the activation of G(i)-protein-coupled receptors. ET(A) receptors mediate vasoconstriction and cell proliferation, whereas ET(B) receptors are important for the clearance of ET-1, endothelial cell survival, the release of nitric oxide and prostacyclin, and the inhibition of ECE-1. ET is activated in hypertension, atherosclerosis, restenosis, heart failure, idiopathic cardiomyopathy, and renal failure. Tissue concentrations more reliably reflect the activation of the ET system because increased vascular ET-1 levels occur in the absence of changes in plasma. Experimental studies using molecular and pharmacological inhibition of the ET system and the first clinical trials have demonstrated that ET-1 takes part in normal cardiovascular homeostasis. Thus, ET-1 plays a major role in the functional and structural changes observed in arterial and pulmonary hypertension, glomerulosclerosis, atherosclerosis, and heart failure, mainly through pressure-independent mechanisms. ET antagonists are promising new agents in the treatment of cardiovascular diseases.
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PMID:Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. 1106

With the advent of more effective therapies for human immunodeficiency virus (HIV) infection, HIV-infected patients are living longer and cardiovascular disease is becoming more obvious in this population. Patients with HIV infection represent one of the most rapidly developing groups with cardiovascular disease globally. Cardiovascular disease complicating HIV infection is likely to contribute to burgeoning healthcare costs. Pericarditis, myocarditis, cardiomyopathy, atherosclerotic coronary vasculopathy, arterial aneurysms, pulmonary hypertension, and endocarditis occur with increased frequency in these patients. Pericardial tamponade, dilated cardiomyopathy, endocarditis, and vasculopathy can lead to fatal outcomes in this population. The advent of cardiomyopathy heralds a very poor prognosis in patients infected with HIV. Coronary vasculopathy without obvious risk factors can lead to myocardial ischemia in young patients infected with the virus. Moreover, the protease inhibitors used to treat HIV infection induce a syndrome of lipodystrophy and dyslipidemia that may be associated with accelerated atherosclerosis as well as insulin resistance. All these factors contribute to increased cardiovascular morbidity and mortality in the HIV-infected population. HIV infection, opportunistic infections, secreted viral proteins such as gp120 (envelope protein) or Tat (transactivator of viral transcription), and cytokines elaborated during the course of HIV infection of the immune system all contribute to pathogenesis of these disorders. Further basic and clinical studies are required to understand the pathogenesis of cardiovascular complications and develop appropriate management strategies for these patients.
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PMID:The cardiovascular and metabolic complications of HIV infection. 1117 4

Vascular repair in response to injury or stress (often referred to as remodeling) is a common complication of many cardiovascular abnormalities including pulmonary hypertension, systemic hypertension, atherosclerosis, vein graft remodeling and restenosis following balloon dilatation of the coronary artery. It is not surprising that repair and remodeling occurs frequently in the vasculature in that exposure of blood, vessels to either excessive hemodynamic stress (e.g. hypertension), noxious blood borne agents (e.g. atherogenic lipids), locally released cytokines, or unusual environmental conditions (e.g. hypoxia), requires readily available mechanisms to counteract these adverse stimuli and to preserve structure and function of the vessel wall. The responses, which were presumably evolutionarily developed to repair an injured tissue, often escape self-limiting control and can result, in the case of blood vessels, in lumen narrowing and obstruction to blood flow. Each cell type (i. e. endothelial cells, smooth muscle cells, and fibroblasts) in the vascular wall plays a specific role in the response to injury. However, while the roles of the endothelial cells and smooth muscle cells (SMC) in vascular remodeling have been extensively studied, relatively little attention has been given to the adventitial fibroblasts. Perhaps this is because the fibroblast is a relatively ill-defined cell which, at least compared to the SMC, exhibits few specific cellular markers. Importantly though, it has been well demonstrated that fibroblasts possess the capacity to express several functions such as migration, rapid proliferation, synthesis of connective tissue components, contraction and cytokine production in response to activation or stimulation. The myriad of responses exhibited by the fibroblasts, especially in response to stimulation, suggest that these cells could play a pivotal role in the repair of injury. This fact has been well documented in the setting of wound healing where a hypoxic environment has been demonstrated to be critical in the cellular responses. As such it is not surprising that fibroblasts may play an important role in the vascular response to hypoxia and/or injury. This paper is intended to provide a brief review of the changes that occur in the adventitial fibroblasts in response to vascular stress (especially hypoxia) and the role the activated fibroblasts might play in hypoxia-mediated pulmonary vascular disease.
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PMID:Hypoxia-induced pulmonary vascular remodeling: contribution of the adventitial fibroblasts. 1119 56

A 12-year-old girl with atrial septal defect combined with pulmonary hypertension and 90% stenosis of the left main coronary artery caused by dilated pulmonary artery was scheduled for atrial septal closure and coronary artery bypass graft under general anesthesia. During the echocardiographic examination to evaluate the anatomical relationship between the pulmonary artery and left main coronary trunk, bradycardia and a depression of ST-segment on electrocardiogram appeared suddenly when the operator compressed the pulmonary artery with a probe of echocardiography from the operative field. The circulatory collapse and ischemic change on electrocardiogram might have been caused by a further reduction of blood flow to the left main coronary trunk narrowed originally by dilated pulmonary artery. Although various etiologies, such as atherosclerosis, syphilis, and congenital abnormalities are widely known to cause stenosis of the left main coronary trunk, external compression by dilated pulmonary artery has not been widely known. Malignant arrhythmias from coronary artery compression with subsequent ischemia could contribute to an incidence of sudden death. Coronary angiography and magnetic resonance imaging are useful for the preoperative evaluation. Careful management is needed to protect such a patient from ischemic event in the perioperative period.
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PMID:[Left main coronary trunk compression by dilated main pulmonary artery in a patient with atrial septal defect]. 1124 76

The endothelin system consists of two G-protein-coupled receptors, three peptide ligands, and two activating peptidases. Its pharmacological complexity is reflected by the diverse expression pattern of endothelin system components, which have a variety of physiological and pathophysiological roles. In the vessels, the endothelin system has a basal vasoconstricting role and participates in the development of diseases such as hypertension, atherosclerosis, and vasospasm after subarachnoid hemorrhage. In the heart, the endothelin system affects inotropy and chronotropy, and it mediates cardiac hypertrophy and remodeling in congestive heart failure. In the lungs, the endothelin system regulates the tone of airways and blood vessels, and it is involved in the development of pulmonary hypertension. In the kidney, it controls water and sodium excretion and acid-base balance, and it participates in acute and chronic renal failure. In the brain, the endothelin system modulates cardiorespiratory centers and the release of hormones. More advanced functional analysis of the endothelin system awaits not only additional pharmacological studies using highly specific endothelin antagonists but also the generation of genetically altered rodent models with conditional loss-of-function and gain-of-function manipulations.
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PMID:Endothelin system: the double-edged sword in health and disease. 1126 79

Endothelin-1 (ET-1) is a powerful vasoconstrictor peptide and regulator of blood flow that plays an important role in blood pressure (BP) elevation in some models of experimental hypertension such as DOCA-salt rat, DOCA-salt-treated spontaneously hypertensive rats (SHR), stroke-prone SHR, Dahl salt-sensitive rats, angiotensin II-infused rats, and one-kidney, one-clip Goldblatt rats, but not in SHR, two-kidney, one-clip hypertensive rats, transgenic (mREN2)27 rats, or Nomega-nitro-L-arginine methyl ester chronically treated rats. In those models of hypertension in which ET-1 plays a vasoconstrictor role, ET-1 was shown to be overexpressed in the vessel walls, or BP has been lowered by administration of ET(A/B)- and ET(A)-selective receptor antagonists. In these experimental models, endothelin receptor antagonists also regressed vascular growth and inflammation, and improved endothelial dysfunction. Hypertensive rats treated with endothelin antagonists were protected from stroke and renal injury. In hypertensive rats without generalized vascular overproduction of ET-1, expression of ET-1 was often enhanced in intramyocardial coronary arteries, suggesting a role of ET in myocardial ischemia in hypertension. Moderate-to-severe hypertensive patients presented enhanced expression of pre-proET-1 mRNA in the endothelium of subcutaneous resistance arteries, suggesting that this stage of hypertension may respond particularly well to endothelin antagonism. In some hypertensive patients, exaggerated vascular responses to ET-1 were found. Hypertensive patients with coronary artery disease have increased arterial expression of ET-1. Increased plasma levels of immunoreactive ET have been described in African Americans. ET-1 plays an important role in atherosclerosis, for which hypertension is an important risk factor, and in ischemic heart disease and stroke. Endothelin-1 may also be involved in other forms of vascular disease, including pulmonary hypertension, after angioplasty restenosis, after allograft vasculopathy, and vasculitis. Thus, ET-1 may participate in vascular damage in cardiovascular disease and in BP elevation in experimental models and in human hypertension. Endothelin antagonists could become effective disease-modifying agents in different forms of cardiovascular disease.
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PMID:Role of endothelin-1 in hypertension and vascular disease. 1141 70


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