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)

Glycosylation of low-density lipoprotein (LDL) is known to be increased in diabetic patients. Recent studies have demonstrated that glycosylated (glc-) LDL contributes to the acceleration of atherosclerosis in diabetes. In the present study, we evaluated the effect of glc-LDL prepared in vitro on platelet aggregation and thromboxane B2 (TxB2) production in washed human platelets and on 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha) production by cultured bovine aortic endothelial cells. After preincubation of washed platelets with glc-LDL or control LDL, thrombin-induced platelet aggregation and TxB2 production were measured. Control LDL enhanced the platelet aggregation rate and TxB2 production in a time- and dose-dependent manner. Glc-LDL showed significantly greater enhancement of those platelet functions than control LDL. On the other hand, while 6-keto-PGF1 alpha production was stimulated by control LDL in a time- and dose-dependent manner, glc-LDL significantly reduced the stimulatory effect of control LDL on 6-keto-PGF1 alpha production. These results suggest that modification of prostaglandin synthesis in platelets and endothelial cells by glycosylated LDL may lead to platelet hyperaggregation and thrombus formation in diabetes.
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PMID:Modification of prostaglandin synthesis in washed human platelets and cultured bovine aortic endothelial cells by glycosylated low density lipoprotein. 263 93

Significant advances have been made in our understanding of the role of the vascular endothelium in preventing thrombosis and in decreasing vascular spasm. The endothelium provides a surface receptor, thrombomodulin, that binds thrombin. In this form, thrombin loses its ability to clot fibrinogen or to aggregate platelets, but is able to activate protein C. In its activated state, protein C is able to act as an inhibitor of coagulation by virtue of its proteolytic destruction of Factors Va and VIIIa. Congenital deficiency of protein C is associated with early and recurrent thrombosis. The discovery that the endothelium is responsible for the production of a short-acting inhibitor of smooth-muscle contraction (EDRF) was a remarkable advance. One of the EDRF substances has been demonstrated to be NO, which has inhibitory effects on both smooth muscle and blood platelets. Activity of EDRF appears to be diminished or lost as a consequence of atherosclerosis, and stimuli that cause vasodilation via the EDRF pathway in normal vessels cause vasoconstriction in atherosclerotic arteries. Regression of atherosclerosis in experimental animals appears to be associated with restoration of EDRF activity.
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PMID:The endothelium, platelets, and coronary vasospasm. 264 64

An increase in plasma fibrinogen content and a decrease in level of antithrombin III in plasma with ageing may cause a thrombotic tendency in the elderly, although the main cause of thrombosis in the aged is atherosclerotic change seen in these subjects. Coagulability of blood is maintained in the so-called therapeutic range in aged patients receiving oral anticoagulant, as well as in younger subjects, however, it has been pointed out that there is an increasing risk of hemorrhage, especially of intracranial hemorrhage, with advancing age. Intracranial hemorrhage is not necessarily a rare complication of anti-platelet or thrombolytic therapy in the aged. Another hazard of aspirin therapy in the aged is the abrupt development of peptic ulcer. The authors administered 40 mg of aspirin per day to ten volunteers. In these subjects, platelets in the venous blood taken in a glass tube were strongly stimulated by coagulating whole blood in the tube for 60 minutes at 37 degrees C. Under this condition, arachidonic acid in platelets was converted to thromboxane B2, which is a stable metabolite of thromboxane A2 that causes platelet aggregation and vasoconstriction to accelerate thrombus formation. After ingestion of the minidose aspirin for one week, the concentration of thromboxane B2 in the serum (not in the plasma) of the volunteers decreased to 7% of the values determined before the administration of the drug, because of inhibition of cyclo-oxygenase in the platelets by aspirin. However, concentration of 6-keto-PGF1 alpha, which is a stable metabolite of prostacyclin that originates from arachidonic acid by cyclo-oxygenase in the vessel wall, did not markedly decrease after the treatment with aspi2+ t-PA and hybrid of t-PA and scu-PA in the aged are discussed. If antithrombotic therapy is always safe in the aged, it may be rational and economical to select subjects predisposed to thrombosis among patients with atherosclerosis. Determination of levels of fibrinogen, beta-thromboglobulin and/or thrombin-antithrombin III complex in plasma may be useful to predict thrombosis.
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PMID:[Antithrombotic drugs]. 267 54

Effects of co-dergocrine mesylate (Hydergine), a drug widely used for the therapy of cerebral vascular disease on local platelet accumulation in the carotid artery region was studied by means of the platelet uptake ratio (PUR) and on the systemic platelet-vascular wall interaction as calculated from platelet half-life were investigated. A placebo controlled, double blind, randomised protocol was used, 18 patients were treated with co-dergocrine and compared to placebo (n = 18). Co-dergocrine treatment resulted in a significant decrease in platelet deposition, PUR decreased from 1.28 +/- 0.05 before treatment to 1.25 +/- 0.06 on day 5 of therapy with a statistically significant (p less than 0.001) in the paired comparison. In the control group the corresponding changes from 1.29 +/- 0.04 before to 1.28 +/- 0.04 did not show a p-value of less than 0.05 in paired comparison. Platelet half-life (72 +/- 11 before vs. 76 +/- 11 hours after 5 days of co-dergocrine treatment) showed a statistically significant (p less than 0.001) prolongation, whereas in the placebo group no relevant change of T/2 was observed (71 +/- 10 before vs. 72 +/- 10 hours on day 5, p greater than 0.10). No relevant effects on ADP-induced platelet aggregation, platelet-release reaction, platelet aggregate ratio, TXB2 plasma levels and thrombin-induced MDA-formation could be detected. These results indicate that co-dergocrine decreased in-vivo platelet residence time to atherosclerotic lesions of the carotid artery. Co-dergocrine may thereby be of benefit in prevention of mural thrombus formation and prevention of transient ischemic attacks, but also of atherosclerosis in man.
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PMID:Effects of Hydergine on platelet deposition on "active" human carotid artery lesions and platelet function. 281 44

We have previously found that vascular relaxation to acetylcholine and thrombin is markedly impaired in vessels from monkeys with diet-induced atherosclerosis. In the present study, we found that both normal and atherosclerotic vessels relaxed completely to the calcium ionophore A23187, which stimulates release of the endothelium-derived relaxing factor by nonreceptor-mediated mechanisms. Atherosclerotic vessels, however, were less sensitive to this agent. The finding that responses to the calcium ionophore were impaired in atherosclerosis suggests that abnormal endothelium-dependent relaxation in atherosclerotic vessels is not related entirely to alterations of thrombin and muscarinic receptors but may also be due to abnormal endothelium-derived relaxing factor production or transfer from the endothelium to the underlying vascular smooth muscle. Neither normal nor atherosclerotic iliac arteries constricted in response to acetylcholine when studied in the nonpreconstricted state. Constriction to acetylcholine in these vessels was not unmasked by removal of the endothelium. Thus, the smooth muscle of iliac vessels from monkeys contains few functioning muscarinic receptors. Impaired relaxation of atherosclerotic vessels to acetylcholine is not due to enhanced muscarinic-mediated constriction or to production of an endothelium-derived constricting factor. In vivo studies were performed to determine if alpha-adrenergic coronary vascular constriction is enhanced in the presence of atherosclerosis. In anesthetized monkeys, myocardial oxygen consumption was increased by two mechanisms, aortic occlusion and phenylephrine infusion. During both aortic occlusion and phenylephrine infusion, decreases in coronary vascular resistance were similar in control and atherosclerotic monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alterations of vascular reactivity in atherosclerosis. 282 87

PAF-acether, a naturally occurring phospholipid, is a potent activator of various biological processes, including platelet aggregation. The mechanisms of action of PAF are largely unknown. We have found that the psychotropic triazolobenzodiazepine drugs, alprazolam and triazolam, potently (IC50 less than 1 microM) inhibit PAF-induced shape change, aggregation and secretion of human platelets. These effects are specific for PAF-activation, since the responses of human platelets to other agonists (ADP, thrombin, epinephrine, collagen, arachidonate and the Ca++ ionophore, A23187) are not inhibited by these triazolobenzodiazepines. The action of triazolobenzodiazepines on PAF-induced platelet function has clinical relevance, especially in diseases where enhanced platelet aggregability may lead to thrombosis and atherosclerosis. In addition, the ability of triazolobenzodiazepines to inhibit other PAF-mediated cellular-responses, such as anaphylactic shock or bronchoconstriction, suggests that these drugs may be useful in preventing several known pathophysiological effects of PAF. The specific antagonism of PAF action by psychotropic drugs also suggests that PAF or PAF-like phospholipids may play a role in neuronal function. This possibility was tested by examining the effects of PAF on neural cells of the clonal line NG108-15, grown in culture in a chemically defined, serum-free medium. Low concentrations of PAF (0.5-2.5 microM) induced neurite extension in NG108-15 cells, whereas higher concentrations (greater than 3 microM) were cytotoxic. Using NG108-15 cells preloaded with aequorin, it was found that PAF causes an increase in intracellular ionized calcium concentration, which is dependent on the presence of extracellular calcium. These results suggest that PAF-induced Ca++ uptake may play a role in neuronal development, and that circulating PAF may contribute to the neuronal degeneration caused by the exposure of neural tissues to blood in situations such as spinal cord injury, trauma, or stroke.
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PMID:Interactions of the alkyl-ether-phospholipid, platelet activating factor (PAF) with platelets, neural cells, and the psychotropic drugs triazolobenzodiazepines. 289 25

Platelets from rats with genetically determined hypercholesterolaemia are hypersensitive to aggregation induced by thrombin compared with platelets from their genetic controls without hypercholesterolaemia. Aggregation or release induced by thrombin of platelets from hypercholesterolaemic and control rats correlated significantly with plasma cholesterol concentrations. Platelet responses to ADP or collagen were not different between the groups. The hypersensitivity to thrombin-induced aggregation was independent of released ADP or products of arachidonic acid metabolism. The changes in platelet sensitivity occurred with only moderate increases in plasma cholesterol concentration and with no detectable changes in total platelet cholesterol. The hypersensitivity of platelets from hypercholesterolaemic rats was not associated with a reduction in platelet survival or any significant injury to the aortic endothelium in these animals. Platelets from hypercholesterolaemic rats were smaller than platelets from controls. Thus, platelets from rats with genetically determined hypercholesterolaemia have alterations in function similar to those found with platelets from rats with diet-induced hypercholesterolaemia indicating that this strain can be used to study the mechanisms by which cholesterol can change platelet function without the possible complicating effects of dietary factors. Since platelet hypersensitivity occurred in rats with genetically determined hypercholesterolaemia without a reduction in platelet survival, these studies are also consistent with the reduced platelet survival found in animals with diet-induced hypercholesterolaemia being independent of platelet changes.
Atherosclerosis 1989 Mar
PMID:Platelet function and survival in rats with genetically determined hypercholesterolaemia. 292 65

There is now considerable evidence to suggest that some aspects of early lesion formation and later lesion growth are a reaction to injury. Hemodynamic factors are important in determining the site of injury and may produce injury directly. Injury can lead to atherogenesis in animal models as well as in humans. Superficial injury exposes the subendothelium, allowing platelet adhesion, which at high shear rates is dependent on vWF. Platelet adhesion and degranulation release PDGF, which stimulates smooth muscle cell proliferation, synthetic functions, and vasoconstriction. LDL stimulates smooth muscle cell growth as well as damages endothelium in some experimental systems. Thus, a link is provided between platelet and lipid involvement in atherosclerosis. Direct evidence for a role of platelets in atherogenesis comes from studies in which animals were treated to reduce platelet number or function or in which platelet function is genetically impaired (pigs with von Willebrand's disease). In these models, reduced platelet function is associated with less atherosclerosis. Deeper injury exposes collagen, with subsequent platelet aggregation, thrombin and fibrin generation. The role of reduced production of PGI2 and fibrinolytic agents following severe damage is unknown. Deep injury to the vessel occurs during plaque fissuring, the pathologic process underlying most cases of myocardial infarction, unstable angina, and some cases of sudden death. Angioplasty produces amelioration of many patients' symptoms and is safe. However, acute occlusion occurs occasionally, and restenosis in the first year occurs in some 30 percent of patients treated. Angioplasty damages the arterial wall, with endothelial denudation and intimal and medial splitting. Why does this, and plaque injury, by stimulating platelet deposition, not produce more restenosis? Changes in arterial anatomy are likely to be important: the increase in vessel diameter and in blood flow produce conditions less favorable for thrombotic or arteriosclerotic restenosis.
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PMID:Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty. 295 94

Restenosis after angioplasty is probably related to 2 processes: thrombosis and recurrence of atherosclerosis. Many approaches to altering these processes are available, but to date none has shown a high rate of success. Heparin has properties relevant to both processes; this makes it an attractive compound for further study. The anticoagulant action of heparin is well known. It is mediated primarily though complex formation with antithrombin III, which leads to a conformational change and an increased rate of thrombin inactivation. Heparin has additional antithrombotic actions, largely mediated through the formation of the same complex, but involving precursor elements such as factor Xa. These actions of heparin can be localized to different portions of the large, complex molecule. Additionally, experimental studies have demonstrated an antiproliferative action of heparin, a property that may be relevant to smooth muscle cell proliferation after angioplasty. This is mediated by a fairly small, functionally distinct nonanticoagulant portion of the heparin molecule. Fragments of heparin possessing particular actions are being investigated experimentally and clinically. Continued investigations of the structure and function of heparin promise to lead to a decreased rate of restenosis and a better understanding of the mechanisms of angioplasty.
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PMID:Anticoagulation and restenosis after percutaneous transluminal coronary angioplasty. 295 35

For a historical survey of the pathogenesis of atherosclerosis the reader is referred to references 1 and 2. Comprehension of the vessel-blood interface homeostasis hinges upon an understanding of the pathophysiology of angio-lymphoid relationships. Even in the smooth contact of the intact hydrophobic intimal lining with the marginal flow of the circulatory stream, small amounts of thrombin and small aggregates of aging platelets float by under physiologic conditions. Since endothelial cells of the vascular intima contain receptors for thrombin, filling these receptors with thrombin becomes a stimulus for the production of prostacyclin (PGI2) by the endothelial cells; PGI2 in turn inhibits adherence of the small platelet aggregates by ADP; homeostasis is maintained. The size of physiologic thrombin-producing platelet microaggregates is controlled by physiologic levels of antithrombin III.
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PMID:Atherosclerosis. I. A leiomyoproliferative disease of the arteries resulting from breakdown of the endothelial barrier to potent blood growth factors. II. Perspectives in atheroprophylaxis. 299 35


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