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)

Accumulation of plasminogen activator inhibitor type 1 (PAI-1) in the arterial wall may accelerate atherogenesis by inhibiting fibrinolysis, diminishing proteolysis of extracellular matrix proteins, or modifying migration of vascular smooth muscle cells. Increased intramural expression of the PAI-1 gene is induced by thrombosis. To determine whether it occurs also in response to a sustained mechanical insult to endothelium, hypercholesterolemia, or both, rabbits were subjected to sustained aortic injury induced by implantation of indwelling polyethylene tubing, to hyperlipidemia induced by cholesterol and peanut oil feeding over a period of 8 weeks, or both. Sustained vascular injury alone did not increase plasma PAI-1. However, hypercholesterolemia with or without mechanically induced vascular injury increased plasma PAI-1 twofold. The expression of PAI-1 mRNA in aorta (Northern blots) was significantly increased when vascular injury was combined with hyperlipidemia. In situ hybridization showed that the increase with mechanical injury alone occurred in endothelial cells covering the neointima (positive for factor VIII and thrombomodulin), in abnormally differentiated vascular smooth muscle cells (positive for embryonic myosin heavy chain), and in macrophages (positive for the RAM-11 anti-macrophage antibody). Qualitatively similar but much more marked increases in PAI-1 gene expression were seen when arterial injury was accompanied by hypercholesterolemia. Neither vitronectin, known to stabilize PAI-1, nor vitronectin mRNA increased in liver. However, immunocytochemistry and Western blots demonstrated marked aortic accumulation of vitronectin protein with hyperlipidemia, particularly in subendothelial fibrotic regions, accompanied by increased neointimal vitronectin mRNA as shown by in situ hybridization. These results suggest that increased synthesis and stabilization of vascular PAI-1 may potentiate accumulation of extracellular matrix, thereby accelerating atherosclerosis.
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PMID:Potentiation by hypercholesterolemia of the induction of aortic intramural synthesis of plasminogen activator inhibitor type 1 by endothelial injury. 769 Mar 10

Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.
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PMID:Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease. 778 64

Due to the incidence of symptomatic atherosclerosis in uremic patients, hemostasis-derived cardiovascular risk factors, basal plasma concentrations of some endothelial-derived glycoproteins and desmopressin-induced variations of endothelial-derived proteins were studied in 22 uremic patients on prolonged maintenance hemodialysis with no cardiovascular antecedent. Compared to control subjects, patients had increased predialysis hemostasis-related cardiovascular risk factors: high fibrinogen, proconvertin, and type 1 plasminogen activator inhibitor plasma concentrations; low albumin values; generally low antithrombin III values but sometimes high. They had high predialysis plasma concentrations of endothelium-derived glycoproteins: von Willebrand factor, tissue-type plasminogen activator and urokinase-type plasminogen activator, which are secreted by endothelial cells, but also soluble thrombomodulin, a marker of endothelial cell injury. The desmopressin-induced release of tissue-type plasminogen activator and of von Willebrand factor were lower than in controls. High fibrinogen, type 1 plasminogen activator inhibitor and low albumin plasma concentrations may be linked to repeated acute phase reactions associated with hemodialysis. Data concerning endothelium-related proteins are concordant with the co-existence of a chronic in vivo endothelial activation and endothelial injury in uremia. This could be linked to the initiation and progression of atherosclerosis.
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PMID:Increased cardiovascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. 799 2

Thrombin, the final product of blood coagulation cascade, shows several effect on the vessel-wall cells. However the effects may be regulated by several thrombin receptors on the endothelium. They include thrombomodulin (TM), protease-Nexin, heparin-like molecule-antithrombin III complex. These binding sites do not transduce the signal of thrombin. Especially TM converts thrombin from a procoagulant protease to an anticoagulant. Recently new thrombin receptor was identified on the endothelium and platelets. Through this receptor, thrombin induces activations both on platelet end-endothelium. In brief platelets aggregate and release several factors including serotonin, PDGF, platelet factor4, beta-thromboglobulin on the stimulation by thrombin. The endothelium release t-PA inhibitor; PAI-1, prostacyclin and endothelin. Thus the activations of these cells by thrombin is a key events in hemostasis, wound healing, inflammation, atherosclerosis and restenosis of coronary artery after PTCA.
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PMID:[Regulation of the endothelial function by thrombomodulin and/or thrombin receptor]. 815 41

Recent advances in determining anti-thrombogenic functions of vascular endothelial cells are reviewed. The following anticoagulant and fibrinolytic systems of endothelial cells are physiologically important; (1) Endothelial cell-derived metabolites including prostacyclin and nitric oxide (NO) support platelet inactivity. (2) Antithrombin III and tissue factor pathway inhibitor (TFPI) bound to heparin-like proteoglycans on endothelial cell membrane inhibit activated serine protease coagulation factors such as thrombin, factor Xa and factor VIIa-tissue factor complex. (3) Thrombomodulin converts thrombin from procoagulant into anticoagulant. Thrombin associated to thrombomodulin on endothelial cells activates protein C. Activated protein C in concert with protein S bound to endothelial cell membrane inactivates factors Va and VIIIa. (4) A receptor for both tissue plasminogen activator and plasminogen on endothelial cells provides an efficient plasmin generating system. Perturbation of these anti-thrombogenic systems of endothelial cells is caused by endotoxin (LPS), cytokines such as interleukin-1 and tumor necrosis factor (TNF), and risk factors for atherogenesis including lipoprotein(a) and homocysteine may result in arterial or venous thrombosis with subsequent development of atherosclerosis.
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PMID:[Anticoagulant and fibrinolytic systems of the injured vascular endothelial cells]. 817 40

The endothelial surface plays an important role in the pathogenesis of atherosclerosis and the regulation of coagulation. It has become increasingly clear that while perturbed endothelial cells generate procoagulant activity, under normal conditions they possess multiple antithrombotic and anticoagulant mechanisms, including generation of prostacyclin and plasminogen activators and synthesis of thrombomodulin as a cell surface cofactor for thrombin-catalyzed activation of protein C. In addition, anticoagulantly active heparan sulfate proteoglycans, including heparin-like molecules are apparently present on the vascular surface. Previous studies showed that homocysteine, a thromboatherogenic and atherogenic agent, inhibits an endothelial thrombomodulin-protein C anticoagulant pathway. We examined whether homocysteine might affect another endothelial anticoagulant mechanism; i.e., heparin-like glycosaminoglycan-antithrombin III interactions. Incubations of cultured endothelial cells with homocysteine reduced the amount of antithrombin III bound to the cell surface in a dose- and time-dependent fashion. In contrast with a marked reduction in the maximal antithrombin III binding capacity, the radioactivity of [35S] sulfate incorporated into heparan sulfate on the cell surface was minimally reduced. Although neither net negative charge nor proportion in total glycosaminoglycans of cell surface heparan sulfate was altered by homocysteine treatment, a substantial reduction in antithrombin III binding capacity of heparan sulfate isolated from homocysteine-treated endothelial cells was found using both affinity chromatography and dot blot assay techniques. The antithrombin III binding activity of endothelial cells decreased after preincubation with homocysteine, cysteine, or 2-mercaptoethanol, containing a sulfhydryl group; no reduction in binding activity was observed after preincubation with methionine, alanine.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Heparan sulfate proteoglycan of endothelial cells: homocysteine suppresses anticoagulant active heparan sulfate in cultured endothelial cells]. 817 41

Endothelium damage is associated with thrombotic risk in a variety of diseases including atherosclerosis, gram negative sepsis, viral infections and neoplastic disease. Therefore, it appears necessary to find a mean for the clinical investigation for such a damage. Among the markers of these cells, thrombomodulin which is a membrane glycoprotein, seems to be of great interest for this purpose. Actually, thrombomodulin is also found in plasma, following an endothelial lesion. Plasma levels of thrombomodulin are increased in a certain number of pathologies associated with endothelium lesion: atheromatous arterial disease, disseminated intravascular coagulation syndrome and also in systemic lupus erythematosus where the levels of plasma thrombomodulin are related to the severity of the pathology. Moreover, previous in vitro studies confirm the fact that the release of thrombomodulin from the endothelial cell membrane occurs during the course of injury by activated leukocytes or hydrogen peroxide. So, one can suppose a prospective interest in the measurement of plasma thrombomodulin as a diagnostic tool for the approach of endothelium damage.
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PMID:Plasma thrombomodulin: new approach of endothelium damage. 820 13

Normal blood fluidity and perpetuation of the non-thrombogenic state are primarily maintained by the anticoagulant and fibrinolytic systems of vascular endothelial cells involving heparin-like molecule, thrombomodulin, prostacyclin, and the receptor for tissue plasminogen activator. Atherosclerosis perturbes these activities, resulting in arterial thrombosis. On the other hand, recent experimental evidence suggests that the disordered thromboregulation often promotes atherosclerosis. Several known risk factors for development of atherosclerosis, including homocysteine and lipoprotein (a) perturb anticoagulant and fibrinolytic systems of vascular endothelial cells at an early stage of atherogenesis.
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PMID:[Coagulation and fibrinolytic systems and atherogenesis]. 841 63

Intracellular protein transport in endothelial cells is selectively inhibited by homocysteine, a thiol amino acid associated with both thrombosis and atherosclerosis. In a previous study, homocysteine decreased cell surface expression of the surface transmembrane glycoprotein thrombomodulin without decreasing secretion of another endothelial cell protein, plasminogen activator inhibitor-1. To define further the effects of homocysteine on protein transport, we examined the processing and secretion of the multimeric glycoprotein von Willebrand factor (vWF) in human umbilical vein endothelial cells. Incubation with 2 mmol/L homocysteine resulted in complete loss of vWF multimers and prevented asparagine-linked oligosaccharide maturation, propeptide cleavage, and secretion; these effects are consistent with impaired exit from the endoplasmic reticulum (ER). Dimerization was only partially inhibited, suggesting that homocysteine causes retention of provWF in the ER without preventing dimer formation. In pulse-chase incubations, intracellular provWF was degraded before exiting the ER in homocysteine-treated cells. Homocysteine also inhibited the processing and secretion of a carboxyl-terminal truncation mutant of human provWF expressed in rat insulinoma cells, indicating that retention in the endoplasmic reticulum can be mediated by regions of provWF apart from the carboxyl-terminal 20-Kd segment. These results suggest that retention of secretory proteins in the ER is regulated by redox mechanisms and imply that the intracellular transport of multiple endothelial cell proteins may be altered in patients with homocystinuria.
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PMID:Homocysteine inhibits von Willebrand factor processing and secretion by preventing transport from the endoplasmic reticulum. 842 60

Growing evidence suggests that moderately elevated levels of homocysteine are associated not only with arterial thrombosis and atherosclerosis but also with venous thrombosis as well. We have reviewed recent studies that indicate that homocysteine inhibits several different anticoagulant mechanisms that are mediated by the vascular endothelium. The protein C enzyme system appears to be one of the most important anticoagulant pathways in the blood. Homocysteine inhibits the expression and activity of endothelial cell surface thrombomodulin, the thrombin cofactor responsible for protein C activation. Homocysteine inhibits the antithrombin III binding activity of endothelial heparan sulfate proteoglycan, thereby suppressing the anticoagulant effect of antithrombin III. Homocysteine also inhibits the ecto-ADPase activity of human umbilical vein endothelial cells (HUVECS). Because ADP is a potent platelet aggregatory agent, this action of homocysteine is prothrombotic. Homocysteine also interferes with the fibrinolytic properties of the endothelial surface because it inhibits the binding of tissue plasminogen activator. Homocysteine stimulates HUVEC tissue factor activity. We have found that lipoprotein(a) [Lp(a)] also stimulates HUVEC tissue factor activity. The combination of Lp(a) plus homocysteine induced more tissue factor activity than either agent alone. These disruptions in several different vessel wall-related anticoagulant functions provide plausable mechanisms for the occurrence of thrombosis in hyperhomocysteinemia.
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PMID:Homocysteine and hemostasis: pathogenic mechanisms predisposing to thrombosis. 864 72


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