UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Plasminogen activator inhibitor-1 (PAI-1) is a rapid inhibitor of tissue plasminogen (tPA) in vivo. Evidence suggests that the level of plasma PAI-1 activity is responsible for the regulation of the whole fibrinolytic process through this tPA/PAI-1 interaction. Levels of PAI-1 have therefore emerged as a candidate for a thrombotic risk factor. Recent epidemiological data supports the view that high plasma levels of PAI-1 may be important in the pathogenesis of arterial and thrombotic disease. These data are reviewed and their significance discussed. PAI-1 expression has been shown to be regulated by many different factors in vitro and the relevance of these data to in vivo physiology is addressed. The current knowledge of the biochemistry, expression and genetics of PAI-1 is also presented and the significance of this to disease pathogenesis is discussed.
Atherosclerosis 1992 Aug
PMID:The status of PAI-1 as a risk factor for arterial and thrombotic disease: a review. 141 86

Plasminogen activator inhibitor-1 (PAI-1), specific inhibitor of plasminogen activators (PA), plays an important role in the regulation of fibrinolysis. Increased levels of PAI-1 have been associated with vascular disease such as thrombosis and atherosclerosis. In the present study the expression of PAI-1 mRNA in human healthy, atherosclerotic and thrombotic blood vessel walls was quantified by RNA-RNA hybridization in solution and localized by in situ hybridization. The mean expression of PAI-1 mRNA was significantly higher in healthy arteries (0.86 pg/microgram total RNA) than in healthy veins (0.29 pg/microgram total RNA), p < 0.01. The mean PAI-1 mRNA expression in thrombotic arteries (1.72 pg/micrograms total RNA) was significantly higher than that in healthy arteries, p < 0.05, and the mean PAI-1 mRNA expression in thrombotic veins (1.29 pg/micrograms total RNA) was significantly higher than that in healthy veins, p < 0.01. By in situ hybridization PAI-1 mRNA was detected in the intima, media and adventitia of healthy arteries and healthy veins. In atherosclerotic arteries PAI-1 mRNA was detected in the atherosclerotic plaque and in the medial and adventitial layers below the plaque. An increased expression of PAI-1 mRNA was found in the intimal layer of a thrombotic vein. The increased expression of PAI-1 mRNA in thrombotic arteries and veins indicates a role for PAI-1 in thrombogenesis.
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PMID:Expression of plasminogen activator inhibitor-1 mRNA in healthy, atherosclerotic and thrombotic human arteries and veins. 790 96

Plasminogen activator inhibitor-1 (PAI-1), a unique member of the serpin superfamily, plays an important role in fibrinolysis and is an established risk factor for cardiovascular diseases. PAI-1 can occur in three interconvertible conformations: an active, a latent and a substrate form. To study conformational and functional relationships in PAI-1, a wide variety of monoclonal antibodies were evaluated for their influence on PAI-1 activity. Out of 77 monoclonal antibodies, directed against human PAI-1, six were selected for their strong inhibitory effect towards PAI-1 activity, i.e., 80 to 100% inhibition in the presence of a 1- to 16-fold molar excess of monoclonal antibody. Detailed analysis of the reaction products formed during the interaction between PAI-1 and its target proteinases tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA), in the presence of these monoclonal antibodies, revealed two distinct mechanisms of PAI-1 inactivation. Incubation of PAI-1 with one series of monoclonal antibodies resulted in the absence of any reaction indicative for direct interaction with the reactive-site loop or a facilitated conversion to the latent conformation. The loss of PAI-1 activity in the presence of the other group of monoclonal antibodies was associated with the concomitant formation of a 41 kDa cleavage product after interaction with the target proteinase. The latter observation demonstrates that binding of these antibodies induced a conformational change thereby converting the inhibitory, active conformation to the non-inhibitory substrate conformation. No conformational changes could be observed in latent PAI-1 under these conditions. Analysis of cross-reactivity revealed that some of these functionally important epitopes were conserved throughout PAI-1 obtained from various species including rabbit mouse and/or pig, resulting in similar functional and conformational effects induced by these antibodies. Thus, we have demonstrated the occurrence of two distinct mechanisms by which the inhibitory activity of PAI-1 can be neutralized. This may have implications for the design of therapeutic or preventive strategies to interfere with PAI-1 activity. Cross-reactivity of these inhibitory antibodies with PAI-1 from various species may also allow their application in experimental animal models studying the in vivo role of PAI-1 in various diseases (e.g. atherosclerosis, thrombosis, angiogenesis,...).
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PMID:Neutralization of plasminogen activator inhibitor-1 inhibitory properties: identification of two different mechanisms. 904 3

Elevated levels of plasma lipoprotein (a) [Lp(a)] have been considered as a strong risk factor for premature cardiovascular diseases. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of plasminogen activators (PA). Increases in PAI-1 levels with or without a reduction in PA levels have been frequently found in coronary artery disease patients. The present paper examined the effects of oxidized Lp(a) on the production of PAI-1 in cultured human umbilical vein endothelial cells (HUVEC). Lp(a) and Lp(a)-free, low density lipoprotein (LDL) were prepared using lysine-Sepharose 4B affinity chromatography. Incubations with 10(-8) M levels of native Lp(a) moderately increased the levels of biologically active PAI-1 in post-culture medium of HUVEC compared to that with equimolar concentrations of native Lp(a)-free LDL. The release of PAI-1 induced by Lp(a) was enhanced by oxidative modification with copper ion. The stimulation of oxidized Lp(a) on PAI-1 production reached plateau in EC treated with 10-20 nM oxidized Lp(a) modified by microM CuSO4. Treatment with 0.2 micrograms/ml of actinomycin D significantly reduced native and oxidized Lp(a)-induced PAI-1 overproduction in EC. Increases in the steady state levels of PAI-1 mRNA were detected in native or oxidized Lp(a)-treated EC. The effect of Lp(a)-free oxidized LDL on PAI-1 production was significantly weaker than the equimolar amount of oxidized Lp(a) but stronger than that of native LDL. Treatments with oxidized Lp(a) increased cell-associated PAI-1 to a similar extent as that in native Lp(a)-treated EC. The results of the present paper demonstrate that oxidative modification enhances Lp(a)-induced PAI-1 production in vascular endothelial cells at RNA transcription level, which suggests that oxidization potentially amplifies the anti-fibrinolytic and thrombotic effect of Lp(a).
Atherosclerosis 1997 Jan 03
PMID:Oxidative modification enhances lipoprotein(a)-induced overproduction of plasminogen activator inhibitor-1 in cultured vascular endothelial cells. 905 Nov 92

Plasminogen activator inhibitor-1 (PAI-1), the major physiologic inhibitor of tissue-type plasminogen activator and urokinase, is abundantly expressed in atherosclerotic vascular wall. To determine the role of PAI-1 in vascular wall, we have used a novel inhibitor of PAI-1, (3E, 4E)-3-benzylidene-4-(3,4,5-trimethoxy-benzylidene) -pyrrolidine-2,5-dione (T-686). T-686 was given to human vascular endothelial cells in vitro and to rabbits subjected to high cholesterol diet and mechanical injury in vivo. T-686 attenuated the augmentation of PAI-1 antigen accumulation induced by transforming growth factor beta in conditioned medium from the human umbilical vein endothelial cells. In rabbits with aortic atherosclerosis induced by hypercholesterolemia and implantation of indwelling plastic tubing, oral administration of T-686 (30mg/kg body weight/day) for 8 weeks attenuated the increase in plasma PAI-1 activity induced by vascular injury without decreasing blood triglyceride and cholesterol. This was accompanied by the reduction in aortic PAI-1 mRNA expression and the inhibition of development of atherosclerosis lesions. Thus, T-686 not only decreased PAI-1 synthesis in vascular cells in vitro but also protected against the development of vascular lesions in vivo. This compound may be useful in defining the role of PAI-1 in atherothrombotic states.
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PMID:A new butadiene derivative, T-686, inhibits plasminogen activator inhibitor type-1 production in vitro by cultured human vascular endothelial cells and development of atherosclerotic lesions in vivo in rabbits. 906 54

The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.
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PMID:Thrombosis and atherosclerosis. 933 57

There is increasing evidence that alterations in metabolism of triglyceride-rich lipoproteins are of importance in the pathogenesis of atherosclerosis and its clinical consequences. Particles with the characteristics of triglyceride-rich lipoprotein remnants have been related to the extent and severity of atherosclerosis in humans and in animal models. These particles can be identified using ultracentrifugal procedures as small, very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) with Svedberg flotation rates (Sf) of 12-60. Postprandial triglyceride levels also have been related to risk of coronary artery disease, consistent with a pathologic role for remnant lipoproteins. In studies in which measurements of lipoprotein subfractions have been carried out, levels of IDL have been more predictive than low-density lipoprotein (LDL) of atherosclerosis progression as assessed by coronary artery angiography or carotid artery ultrasonography. These findings suggest that a considerable portion of the coronary disease risk attributed to LDL may be accounted for by the IDL particles included in standard LDL measurements. Other metabolic changes associated with increased levels of plasma triglyceride may also adversely affect cardiovascular disease risk. These include reductions in HDL-cholesterol and apoprotein A1, increased levels of small dense LDL particles, redistribution of apoC-III from HDL to apoB-containing lipoproteins, diminished insulin sensitivity, and procoagulant changes, including increased levels of the fibrinolysis inhibitor, plasminogen-activator inhibitor-1 (PAI-1). A predominance of small dense LDL (subclass pattern B) is a discrete marker for this cluster of interrelated abnormalities and is found in 40-50% of patients with coronary artery disease. Therapeutic interventions with favorable effects on components of this dysmetabolic profile appear to be of value in decreasing atherosclerosis risk in a substantial proportion of the population.
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PMID:Atherogenicity of triglyceride-rich lipoproteins. 952 8

Plasminogen activator inhibitor-1 (PAI-1) plasma levels have been consistently related to a polymorphism (4G/5G) of the PAI-1 gene. The renin-angiotensin pathway plays a role in the regulation of PAI-1 plasma levels. An insertion (I)/deletion (D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been related to plasma and cellular ACE levels. In 1032 employees (446 men and 586 women; 22 to 66 years old) of a hospital in southern Italy, we investigated the association between PAI-1 4G/5G and the ACE I/D gene variants and plasma PAI-1 antigen levels. None of the individuals enrolled had clinical evidence of atherosclerosis. In univariate analysis, PAI-1 levels were significantly higher in men (P<.001), alcohol drinkers (P<.001), smokers (P=.009), and homozygotes for the PAI-1 gene deletion allele (4G/4G) (P=.012). Multivariate analysis documented the independent effect on PAI-1 plasma levels of body mass index (P<.001), triglycerides (P<.001), sex (P<.001), PAI-1 4G/5G polymorphism (P=.019), smoking habit (P=.041), and ACE I/D genotype (P=.042). Thus, in addition to the markers of insulin resistance and smoking habit, gene variants of PAI-1 and ACE account for a significant portion of the between-individual variability of circulating PAI-1 antigen concentrations in a general population without clinical evidence of atherosclerosis.
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PMID:PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis: relation to environmental and genetic determinants. 955 61

Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of both tissue-type and urokinase-type plasminogen activators. The balance between plasminogen activators and PAI-1 plays an important role in several physiological and pathophysiological processes such as atherosclerosis or thrombosis. Because these conditions are associated with hypoxia, it was the aim of the present study to investigate the influence of low O(2) tension on the expression of PAI-1 mRNA and protein using primary cultured rat hepatocytes as a model system. We found that PAI-1 mRNA and protein were induced by mild hypoxia (8% O(2)). The hypoxia-dependent PAI-1 mRNA induction was transcriptionally regulated because it was inhibited by actinomycin D (ActD). Luciferase (LUC) reporter gene constructs driven by about 800 bp of the 5'-flanking region of the rat PAI-1 gene were transiently transfected into primary rat hepatocytes; mild hypoxia caused a 3-fold induction, which was mediated by the PAI-1 promoter region -175/-158 containing 2 putative hypoxia response elements (HRE) binding the hypoxia-inducible factor (HIF-1). Mutation of the HRE-1 (-175/-168) or HRE-2 (-165/-158) also abolished the induction by mild hypoxia. Cotransfection of a HIF-1alpha vector and the PAI-1-LUC constructs, as well as gel shift assays, showed that the HRE-2 of the PAI-1 promoter was most critical for induction by hypoxia and HIF-1 binding. Thus, PAI-1 induction by mild hypoxia via a HIF-1 binding HRE in the rat PAI-1 promoter appears to be the mechanism causing the increase in PAI-1 in many clinical conditions associated with O(2) deficiency.
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PMID:Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. 1059 62

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers share a number of common properties, including their ability to lower blood pressure. However, they can be differentiated based on their individual effects on the renin-angiotensin system, the fibrinolytic system and the actions of bradykinin. They act at different points in the cascade of events that constitute the renin-angiotensin system. In animal models of atherosclerosis, ACE inhibition was associated with a significant reduction in the percentage surface area of lesions, while no similar effect was evident with AT1 receptor blockade. In the fibrinolytic system, both ACE inhibition and AT1 receptor blockade were associated with reduced aldosterone levels, although the effect was greater with ACE inhibition; only ACE inhibition was associated with a significant reduction in plasminogen activation inhibitor-1. By blocking the degradation of bradykinin, ACE inhibitors potentiate the ability of bradykinin to reduce blood pressure and stimulate the release of tissue-type plasminogen activator from the vasculature, an effect not seen with AT1 receptor blockers.
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PMID:Pharmacology of ACE inhibitors versus AT1 blockers. 1090 25

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