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)

Endothelial dysfunction, or activation, elicited by oxidized LDL (Ox-LDL) or its lipid constituent, has been implicated in the initiation and progression of atherosclerosis. We have recently identified a C-type lectin-like molecule, designated lectin-like Ox-LDL receptor-1 (LOX-1), which acts as a cell-surface receptor for Ox-LDL in cultured vascular endothelial cells. In this study, we provide evidence that LOX-1 expression can be upregulated by tumor necrosis factor-alpha (TNF-alpha) and phorbol 12-myristate 13-acetate (PMA) in cultured bovine aortic endothelial cells. TNF-alpha and PMA upregulated LOX-1 protein and mRNA in a time- and dose-dependent manner. Nuclear runoff assay revealed that TNF-alpha stimulates transcription of the LOX-1 gene. Chinese hamster ovary K1 cells stably expressing LOX-1 internalized 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI)-labeled Ox-LDL but did not significantly internalize acetylated LDL (Ac-LDL), which was effectively suppressed by excess amounts of unlabeled Ox-LDL but not by Ac-LDL. Upregulated expression of LOX-1 by TNF-alpha and PMA was associated with increased uptake of DiI-Ox-LDL that cannot be blocked by excess amounts of unlabeled Ac-LDL. Taken together, LOX-1 is a receptor specific for Ox-LDL, and enhanced uptake of Ox-LDL via this novel receptor on vascular endothelial cells may play an important role in endothelial activation in atherogenesis.
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PMID:Inducible expression of lectin-like oxidized LDL receptor-1 in vascular endothelial cells. 971 Jan 25

Research has established endothelial dysfunction as a pathophysiological mechanism underlying many cardiovascular disease processes. Tissue angiotensin-converting enzyme (ACE) plays a central role in regulating processes that contribute to endothelial function and cardiovascular disease. A number of large clinical studies have demonstrated conclusively the beneficial effects of ACE inhibition in patients with myocardial ischaemia and left ventricular dysfunction, including a significant reduction in the risk of recurrent myocardial infarction. Mechanistic findings from these studies indicated that the beneficial effects of ACE inhibition would extend to patients with preserved left ventricular function. Available results suggest that ACE inhibition with quinapril improves endothelial function in large and small vessels in patients with coronary artery disease and preserved left ventricular function. Quinapril also inhibits progression of coronary atherosclerosis in patients with high levels of low-density lipoprotein cholesterol (> or = 130 mg.dl-1) and reverses the toxic effects of smoking on endothelial function. Endothelial dysfunction also may be an important mechanism in episodes of angina and silent ischaemia. The central role of tissue ACE in endothelial function suggests that ACE inhibition has antiischaemic effects. A study in progress, the QUinapril Antiischaemia and Symptoms of Angina Reduction trial, addresses shortcomings in earlier studies of ACE inhibition for ischaemia and is expected to define the role of quinapril in ischaemia.
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PMID:Rationale for ACE inhibition as an anti-ischaemic therapy. 971 54

Vascular responses of human intramyocardial small arteries were examined in vitro to assess the influence of atherosclerosis and risk factors for coronary artery disease on endothelium-dependent relaxation. Recipient hearts were obtained from patients with ischemic (n = 14) and nonischemic (n = 13) cardiomyopathy undergoing heart transplantation. Small intramyocardial coronary arteries (mean internal diameter 313 +/- 11 micrometers) were mounted on a wire myograph for measurement of morphology and isometric tension. Vasodilation was examined after preconstriction with U-46619, a thromboxane A2 analog. Endothelium-dependent relaxation to acetylcholine and bradykinin was impaired in patients with ischemic compared with nonischemic cardiomyopathy (P < 0.01 and P < 0.001, respectively). Endothelium-independent relaxation to sodium nitroprusside was preserved. Incubation with L-arginine (3 mmol/l) did not improve endothelium-dependent relaxation to acetylcholine or bradykinin. With the use of stepwise multivariate analysis, hypercholesterolemia, but no other risk factor for atherosclerosis, was independently associated with impaired endothelium-dependent relaxation to acetylcholine (r = -0.50, P = 0.05) but not to bradykinin. Endothelial dysfunction in intramyocardial small arteries may predispose patients with nonobstructive epicardial atherosclerosis and hypercholesterolemia to myocardial ischemia.
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PMID:Endothelial dysfunction in human intramyocardial small arteries in atherosclerosis and hypercholesterolemia. 974

Endothelial dysfunction, or activation, elicited by oxidized low density lipoprotein (Ox-LDL) and its lipid constituents has been shown to play a key role in the pathogenesis of atherosclerosis. We recently have identified a novel receptor for Ox-LDL-designated lectin-like Ox-LDL receptor (LOX-1) in vascular endothelial cells. To examine ligand specificity of LOX-1, we established CHO cell lines stably expressing both human and bovine LOX-1 (LOX-1-CHO). LOX-1-CHO bound and degraded 125I-labeled Ox-LDL but did not significantly degrade 125I-labeled acetylated LDL (Ac-LDL). Fucoidin and maleylated BSA (M-BSA), which inhibit 125I-Ox-LDL binding to class A scavenger receptors, did not inhibit 125I-Ox-LDL binding or degradation in LOX-1-CHO. Polyinosinic acid and carrageenan, in contrast, significantly reduced 125I-Ox-LDL binding to LOX-1-CHO by 62% and 60%, respectively. Delipidated and untreated 125I-Ox-LDL were bound and degraded equally in LOX-1-CHO; furthermore, excess amounts of unlabeled, delipidated Ox-LDL inhibited binding and degradation of untreated 125I-Ox-LDL. Taken together, LOX-1 is a receptor for Ox-LDL but not for Ac-LDL. LOX-1 recognizes protein moiety of Ox-LDL, and its ligand specificity is distinct from other receptors for Ox-LDL, including class A and B scavenger receptors.
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PMID:Ligand specificity of LOX-1, a novel endothelial receptor for oxidized low density lipoprotein. 976 24

A strong relationship between hypercholesterolemia and atherosclerosis has been established through epidemiological, experimental, and clinical trial data. Traditional theories on the pathophysiology of this relationship involve the deposition, modification, and cellular uptake of cholesterol, and the release of inflammatory and growth factors resulting in smooth muscle cell proliferation and collagen matrix production. The vasculature has recently been found to be an active and complex organ, with the endothelium playing a controlling role in vascular tone, lipid breakdown, thrombogenesis, inflammation, and vessel growth. In the presence of risk factors such as hypercholesterolemia, the endothelium promotes vasoconstriction, monocyte and platelet adhesion, thrombogenesis, and growth factor release. A high-fat diet also directly impairs endothelial function and increases coagulation factors. Endothelial dysfunction is associated with decreased availability of the predominant vasodilator nitric oxide, possibly by increased destruction by oxygen free radicals. This dysfunctional state appears before the earliest anatomic evidence of atherosclerosis and may represent an important initial step in its development. Several studies have shown improvements in endothelial function with cholesterol lowering in both normal individuals and those with coronary heart disease. Short-term improvements in endothelial-dependent vasodilation and adhesion molecule expression have also been reported with antioxidant therapy. These observations suggest that atherosclerosis is at least in part caused by endothelial dysfunction that favors cellular proliferation. This new understanding helps to explain the early and substantial reductions in major cardiovascular events associated with cholesterol lowering.
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PMID:Cholesterol, cholesterol lowering, and endothelial function. 979 Apr 13

Endothelial dysfunction in non-insulin dependent (Type 2) diabetes mellitus (NIDDM) has implications for the pathogenesis of the two major complications, macrovascular disease and microangiopathy. Endothelial dysfunction is a consequence of a disturbance in the L-arginine/nitric oxide pathway. Its occurrence in NIDDM is well supported by both in vitro and in vivo studies. NIDDM results in diverse abnormalities in lipoprotein metabolism, the most significant being hypertriglyceridaemia which is associated with increased plasma concentrations of small dense LDL and low levels of HDL. Dysglycaemia results in hyperoxidative stress and increased formation of advanced-glycosylation endproducts, both of which enhance the oxidative modification of lipoprotein particles. Based on extensive in vitro studies and on human data, we generate the hypothesis that the development of endothelial dysfunction in NIDDM is a consequence of the effect of dyslipoproteinaemia, in particular increased circulatory concentrations of modified small dense LDL and of hyperoxidative stress on the formation, action and disposal of nitric oxide, by diverse molecular mechanisms; HDL is proposed to have a protective effect on these processes through its enzymic antioxidant properties. The hypothesis proposed is simple, testable and consistent with wide sources of evidence. The practical implications of the hypothesis and the existing opportunities for the prevention and reversal of endothelial dysfunction in NIDDM are also reviewed and discussed.
Atherosclerosis 1998 Nov
PMID:Dyslipoproteinaemia and hyperoxidative stress in the pathogenesis of endothelial dysfunction in non-insulin dependent diabetes mellitus: an hypothesis. 986 35

Endothelial dysfunction appears to be a key early event in a number of important cardiovascular disease states, including atherosclerosis and hypertension. Testing endothelial function in vivo has proved challenging. Although the endothelium releases a number of products, no single blood test has yet proved useful to determine normal endothelial function or early abnormalities. The most common test of endothelial function used to date in vivo depends on measuring endothelium-dependent dilatation in response to pharmacologic or physiologic stimuli. This depends mostly on the endothelial ability to release nitric oxide (NO), not only a potent vasodilator but also an inhibitor of platelet aggregation, monocyte adhesion, and smooth muscle proliferation. Over the past decade, endothelium-dependent dilatation has been tested using high-resolution external vascular ultrasound. The major advantage of this method is that it is completely noninvasive, accurate, and reproducible. The major disadvantage is that the coronary arteries cannot be imaged directly with ultrasound, and therefore the test is usually applied to peripheral arteries, such as the brachial or femoral conduit vessels. Using such ultrasound techniques, many groups have documented endothelial dysfunction in children and young adults at risk for atherosclerosis and have performed a variety of studies concerning reversibility of early arterial damage, using potentially important antiatherogenic strategies.
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PMID:Testing endothelial function using ultrasound. 988 44

The endothelium synthesizes and releases several vasodilating factors, including nitric oxide, endothelium-derived hyperpolarizing factor, and prostacyclin. Under certain conditions, it also liberates vasocontracting factors. Thus, the endothelium plays an important role in regulating vascular homeostasis. Several intracellular mechanisms are involved in the synthesis of nitric oxide, including receptor-coupled G proteins, the availability of L-arginine, cofactors for endothelial nitric oxide synthase and the expression of the enzyme. Endothelial dysfunction by aging, menopause and hypercholesterolemia is involved in the development of atherosclerotic vascular lesions, and predisposes the blood vessel to several vascular disorders, such as vasospasm and thrombosis. Multiple mechanisms are apparently involved in the pathogenesis of the endothelial dysfunction in atherosclerosis. The reduced production of nitric oxide by the endothelium is caused by abnormalities in endothelial signal transduction, availability of L-arginine, cofactors for endothelial nitric oxide synthase and expression of the enzyme. Other mechanisms may also be involved in the impaired endothelium-dependent relaxations in atherosclerosis, including increased destruction of nitric oxide by superoxide anion, altered responsiveness of vascular smooth muscle, and concomitant release of vasocontracting factors. In addition to the treatment of the underlying risk factors, several pharmacological agents can improve endothelial dysfunction in atherosclerosis. Thus, the endothelium is a novel therapeutic target for the treatment of atherosclerotic cardiovascular disease.
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PMID:Primary endothelial dysfunction: atherosclerosis. 1007 13

Endothelial dysfunction is thought to be an important early event in atherogenesis, related in part to reduced bioavailability of nitric oxide in the arterial wall. Endothelial function may be impaired in the presence of oxidised low density lipoprotein. The use of vitamin E as an anti-oxidant might enhance the bioavailability of nitric oxide in this situation. The effect of vitamin E 1000 IU/day on arterial endothelial physiology was studied in 20 asymptomatic older subjects, aged 45-70 years, who showed evidence of age-related endothelial dysfunction. Endothelial function was assessed non-invasively using brachial ultrasound and the primary outcome measure was flow-mediated endothelium-dependent dilatation (FMD) in response to reactive hyperaemia. A double-blind, placebo-controlled, randomised crossover design was employed. After 3 weeks of stabilisation on a standard fat-reduced diet, subjects received vitamin E or placebo for 10 weeks in random order, separated by a washout period of 8 weeks. There were no significant changes in blood pressure, plasma lipid or lipoprotein concentrations. Plasma alpha-tocopherol increased from 50+/-3 (mean+/-S.E.M.) to 91+/-6 micromol/l (P < 0.001) with vitamin E ingestion. Total plasma F2alpha-isoprostanes, a measure of free radical-induced lipid peroxidation, were not altered by vitamin E ingestion (0.86+/-0.26 versus 0.82+/-0.25 nmol/l, P > 0.6). FMD was not significantly different between the placebo and vitamin E periods (2.7+/-0.6% versus 2.4+/-0.4%). Variation in FMD was not correlated with change in plasma alpha-tocopherol (r = - 0.03, P > 0.8). The study was powered to detect a minimum change in FMD of 2%. Glyceryl trinitrate endothelium-independent dilatation was not significantly changed with vitamin E (13.7+/-1.3% versus 13.6+/-1.4%,). These results exclude a major impact of medium-term supplementation with vitamin E on arterial endothelial function when age-related dysfunction is already present.
Atherosclerosis 1999 Mar
PMID:Vitamin E ingestion does not improve arterial endothelial dysfunction in older adults. 1020 95

Abnormalities in vascular endothelial function, which occur early in atherosclerosis, may play an etiologic role in the development of the disease or represent a marker for the extent of atherosclerosis. Endothelial dysfunction, usually characterized by demonstration of decreased endothelium-dependent vasorelaxation, may be a sensitive and specific method to detect vascular disease in its earliest stages. In this context, separation of abnormalities in receptor-mediated and flow-mediated endothelium-dependent vasodilatory responses may allow for the most accurate characterization of endothelial dysfunction. In 35 patients undergoing routine annual cardiac catheterization after heart transplantation, changes in epicardial lumen area and coronary blood flow in response to intracoronary administration of adenosine, acetylcholine, and nitroglycerin were measured simultaneously using an intravascular ultrasound (IVUS) catheter positioned over a Doppler flow wire in the left anterior descending coronary artery. The combination of these techniques allowed for distinction between receptor-mediated and flow-mediated endothelium-dependent vascular responses. Peak flow with the endothelium-independent resistance vessel dilator adenosine occurred at 18+/-2 sec; the maximal lumen area response occurred later, at 43+/-11 sec (P < 0.001). Acetylcholine, an endothelium-dependent small- and large-vessel vasodilator, caused an immediate increase in both flow and lumen area, but a second peak of dilation was observed, and maximal area occurred 46 sec after maximal flow (54+/-14 vs. 100+/-26 sec, P < 0.001). Simultaneous IVUS and Doppler flow measurements after infusion of vasoactive agents allows for distinction between and evaluation of the relative contribution of agonist-mediated and flow-mediated responses, which may offer important and unique insights into coronary endothelial function.
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PMID:Simultaneous intracoronary ultrasound and Doppler flow studies distinguish flow-mediated from receptor-mediated endothelial responses. 1034 24


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