Enhanced procoagulatory activity (PCA) of human monocytes/macrophages after in vitro stimulation with chemically modified LDL

Schuff‐Werner, P.; Claus, George; Armstrong, Victor W.; Köstering, H.; Seidel, D.

doi:10.1016/0021-9150(89)90214-1

Cited by 57 publications

(31 citation statements)

References 12 publications

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“…oxLDL and other bioactive lipids induce expression of the procoagulant protein tissue factor (TF) in monocytes/macrophages, endothelial cells, and smooth muscle cells (20)(21)(22)(23)(24). Consistent with these in vitro observations, high levels of TF are present in human and mouse atherosclerotic plaques (25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 78%

Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

Owens¹,

Passam²,

Antoniak³

et al. 2012

J. Clin. Invest.

163

138

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Hypercholesterolemia is a major risk factor for atherosclerosis. It also is associated with platelet hyperactivity, which increases morbidity and mortality from cardiovascular disease. However, the mechanisms by which hypercholesterolemia produces a procoagulant state remain undefined. Atherosclerosis is associated with accumulation of oxidized lipoproteins within atherosclerotic lesions. Small quantities of oxidized lipoproteins are also present in the circulation of patients with coronary artery disease. We therefore hypothesized that hypercholesterolemia leads to elevated levels of oxidized LDL (oxLDL) in plasma and that this induces expression of the procoagulant protein tissue factor (TF) in monocytes. In support of this hypothesis, we report here that oxLDL induced TF expression in human monocytic cells and monocytes. In addition, patients with familial hypercholesterolemia had elevated levels of plasma microparticle (MP) TF activity. Furthermore, a high-fat diet induced a time-dependent increase in plasma MP TF activity and activation of coagulation in both LDL receptor-deficient mice and African green monkeys. Genetic deficiency of TF in bone marrow cells reduced coagulation in hypercholesterolemic mice, consistent with a major role for monocyte-derived TF in the activation of coagulation. Similarly, a deficiency of either TLR4 or TLR6 reduced levels of MP TF activity. Simvastatin treatment of hypercholesterolemic mice and monkeys reduced oxLDL, monocyte TF expression, MP TF activity, activation of coagulation, and inflammation, without affecting total cholesterol levels. Our results suggest that the prothrombotic state associated with hypercholesterolemia is caused by oxLDL-mediated induction of TF expression in monocytes via engagement of a TLR4/TLR6 complex.

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Section: Introductionmentioning

confidence: 78%

Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

Owens¹,

Passam²,

Antoniak³

et al. 2012

J. Clin. Invest.

163

138

View full text Add to dashboard Cite

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“…Many of these have been shown to be able to induce TF expression in monocytes or monocytic cells in culture either directly (agonists) or indirectly (cell-cell contact). 34,38 In some but not all studies, it has been reported that modified lipoproteins also stimulate or induce TF expression in monocytes/macrophages, 39,40,50,51 although the presence of contaminating endotoxin levels has not been excluded in all studies. 40 Most of these studies have examined the effect of modified lipoproteins on TF expression in monocytes/macrophages by using monocytes isolated by adherence to plastic and cultured while adherent.…”

Section: Discussionmentioning

confidence: 99%

“…In all other studies dealing with the effects of modified lipoproteins on TF expression, adherent cells have been used. 39,40,50,51 Therefore, it cannot be excluded that adhesion-related responses play a role in the induction and stimulation of TF expression by lipoproteins. When monocytes or monocytic THP-1 cells were adhered to fibrin or fibronectin, some induction of TF was observed, 78,79 suggesting that under certain conditions adhesion itself is already able to induce TF expression to some extent.…”

Section: Discussionmentioning

confidence: 99%

“…In earlier studies, similar experiments have been performed with monocytes that were isolated by adherence and cultured under adherent conditions. 39,40,50,51 , and ␤-VLDL) on TF expression (mRNA, antigen, and activity) and lipid accumulation. Previously, we demonstrated that these cells, which show stable expression of macrophage-specific markers (CD71, the mannose receptor, the scavenger receptors types I and II), do not express significant amounts of TF.…”

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confidence: 99%

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Cholesterol or Triglyceride Loading of Human Monocyte-Derived Macrophages by Incubation With Modified Lipoproteins Does Not Induce Tissue Factor Expression

Eijnden

Noort

Hollaar

et al. 1999

ATVB

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Abstract-Macrophages/foam cells localized in cholesterol-and triglyceride-rich regions of atherosclerotic plaques express high levels of tissue factor (TF), the essential cofactor and receptor of factor VIIa. It is not clear whether modified lipoproteins, for which several agonistic effects on macrophages have been described, are independent stimuli of TF expression in these cells. Therefore, we studied the effect of short-term (1 day) and long-term (4 to 7 days) incubation of human monocyte-derived macrophages cultured in suspension with modified and native LDLs or VLDLs on the expression of TF mRNA, antigen, and activity. We used native LDL or VLDL, moderately oxidized LDL or VLDL, severely oxidized LDL or VLDL, acetylated LDL, and ␤-VLDL at a protein concentration of 100 g/mL. Cholesterol loading occurred within 9 hours after the addition of acetylated LDL and continued during long-term incubation. Incubation of severely oxidized LDL for 7 days resulted in a slight increase in cholesterol content.

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“…13 However, in vitro studies on effects of cholesterol on TF expression gave conflicting results. Cholesterol loading, by exposing monocytes/macrophages or endothelial cells to modified LDL or cholesterol, was shown to induce TF expression in some studies, [14][15][16][17][18][19] whereas no effect was found in other studies. [20][21][22][23] Most of these previous studies were focused primarily on investigating the role of LDL or cholesterol in modulating transcriptional or translational regulation of TF.…”

Section: Introductionmentioning

confidence: 99%

Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol

Mandal

Iakhiaev

Pendurthi

et al. 2005

Blood

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Cholesterol, in addition to providing rigidity to the fluid membrane, plays a critical role in receptor function, endocytosis, recycling, and signal transduction. In the present study, we examined the effect of membrane cholesterol on functional expression of tissue factor (TF), a cellular receptor for clotting factor VIIa. Depletion of cholesterol in human fibroblasts (WI-38) with methyl-␤-cyclodextrin-reduced TF activity at the cell surface. Binding studies with radiolabeled VIIa and TF monoclonal antibody (mAB) revealed that reduced TF activity in cholesterol-depleted cells stems from the impairment of VIIa interaction with TF rather than the loss of TF receptors at the cell surface. Repletion of cholesterol-depleted cells with cholesterol restored TF function. Loss of caveolar structure on cholesterol removal is not responsible for reduced TF activity. Solubilization of cellular TF in different detergents indicated that a substantial portion of TF in fibroblasts is associated with noncaveolar lipid rafts. Cholesterol depletion studies showed that the TF association with these rafts is cholesterol dependent. Overall, the data presented herein suggest that membrane cholesterol functions as a positive regulator of TF function by maintaining TF receptors, probably in noncaveolar lipid rafts, in a high-affinity state for VIIa binding. IntroductionCholesterol is a lipid precursor for steroid hormones and bile salts and is present in cell membranes and circulation. Cholesterol in the membrane regulates flexibility and mechanical stability of the membrane. 1 Further, cholesterol plays a critical role in differentiating and maintaining cell surface microdomains of differing lipid composition, particularly sphingolipid rafts. Lipid rafts are shown to contribute to the regulation of various cellular functions, including receptor function, endocytosis, intracellular trafficking of receptors, and signaling pathways. [2][3][4][5] Tissue factor (TF) is the cellular receptor for clotting factor VIIa, and the formation of TF-VIIa complexes on cell surfaces triggers the coagulation cascade. 6 Studies suggest that exposure of TF to circulating blood on rupture of atherosclerotic plaque plays an important role in the pathogenesis of thrombus formation at sites of plaque rupture, resulting in acute coronary events and myocardial infarction. [7][8][9][10] Since cholesterol/ oxidatively modified low-density lipoprotein (LDL) present in atherosclerotic plaques is thought to play an important role in the atherogenesis through its biologic effects, including TF expression, many earlier studies were focused on investigating the effect of cholesterol on TF expression. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, widely used to suppress plasma LDL cholesterol levels in patients with primary hypercholesterinemia, were shown to inhibit TF expression in both in vitro and in vivo. 11,12 Consistent with this, dietary lipid lowering was found to reduce TF expression in rabbit atheroma. 13 However, in vitro studies on...

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Enhanced procoagulatory activity (PCA) of human monocytes/macrophages after in vitro stimulation with chemically modified LDL

Cited by 57 publications

References 12 publications

Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

Monocyte tissue factor–dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin

Cholesterol or Triglyceride Loading of Human Monocyte-Derived Macrophages by Incubation With Modified Lipoproteins Does Not Induce Tissue Factor Expression

Acute cholesterol depletion impairs functional expression of tissue factor in fibroblasts: modulation of tissue factor activity by membrane cholesterol

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