Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor–Positive Microvesicles

Liu, Ming-Lin; Reilly, Michael P.; Casasanto, Peter; McKenzie, Steven E.; Williams, Kevin Jon

doi:10.1161/01.atv.0000254674.47693.e8

Cited by 109 publications

(112 citation statements)

References 59 publications

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…32 Furthermore, according to the recent report by Liu et al, cholesterol activates monocytes, which leads to the increased TF synthesis and its release with membrane microparticles into the systemic circulation. 33 Monocytosis and increased levels of TF on circulating monocytes are also characteristic hematologic findings in patients with antiphospholipid syndrome associated with recurrent thromboses. [34][35][36] Thus, our data give novel insights into better understanding of several clinical conditions associated with high monocyte counts and thrombogenic potential of the blood.…”

Section: Discussionmentioning

confidence: 99%

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Egorina

Sovershaev

Olsen

et al. 2008

Blood

107

View full text Add to dashboard Cite

Unlike unanimous opinion on tissue factor (TF) expression in monocytes, the quest for TF presence in granulocytes has been going on for decades. To study the cell origin and track the blood-borne TF, we assessed TF activity and protein levels, knocked-down endogenous TF expression with small interfering RNA (siRNA), and overexpressed TF-yellow fluorescent protein (TF-YFP) fusion in immunologically isolated human monocytes and granulocytes. Monocytes and, to a much lesser extent, granulocytes isolated from lipopolysaccharide (LPS)/ phorbol 12-myristate-13-acetate (PMA)-stimulated whole blood contained active TF antigen. However, only monocytes possessed significant TF activity and protein levels when stimulated with LPS/PMA in suspension. Reintroduction of TF-silenced monocytes to whole blood led to a profound reduction of LPS/PMA-stimulated TF activity in both mononuclear cell (MNC) and granulocyte fractions. No reduction in TF activity in MNC and granulocyte fractions was observed when TFsilenced granulocytes were reintroduced to whole blood. As shown by immunoblotting, flow cytometry, and confocal microscopy, granulocytes became positive for TF-YFP when isolated from whole blood reconstituted with TF-YFP-expressing monocytes. Together, we pinpoint monocytes as a major source of TF and provide solid experimental evidence for a direct transfer of TF protein from the monocytes to granulocytes in the blood. IntroductionThe source of tissue factor (TF) among circulating blood leukocytes still remains a mystery that is bolstered by several conflicting reports. 1-7 TF is a 45-kDa membrane glycoprotein that binds to factor F VII (FVII)/FVIIa with high affinity. 8 The formation of TF-FVIIa complexes triggers the coagulation cascade by activating both factors IX and X, which leads to thrombin generation and stimulates platelet activation and fibrin deposition. [9][10][11] Under physiologic conditions, TF is absent in the cells and tissues located on the interface with circulating blood. It is constitutively expressed in vascular cell types that have no direct contact with blood, such as adventitial fibroblasts, pericytes, and smooth muscle cells. 12 This mode of expression provides a haemostatic protection should vascular injury occur. In 1989, Drake et al created a concept of TF as being a "haemostatic envelope ready to activate coagulation when vascular integrity is disrupted." 13 Although studies demonstrating the presence of TF on circulating blood cells began in the early 1970s, the question of which blood cell type expresses TF is still a matter of considerable discussion. 14,15 To date, neutrophils, eosinophils, platelets, and even lymphocytes were shown to be positive for TF protein under diverse conditions. [2][3][4][5][6][7] In our present study, we studied TF procoagulant activity and antigen in highly pure resting and stimulated monocytes and granulocytes under conditions of whole blood and plating. Having used small interfering RNA (siRNA)-mediated knockdown of endogenous TF expression in freshly isolated ...

show abstract

Section: Discussionmentioning

confidence: 99%

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Egorina

Sovershaev

Olsen

et al. 2008

Blood

107

View full text Add to dashboard Cite

show abstract

“…Interestingly, acute coronary syndrome patients have elevated levels of monocyte-derived MPs and TF + MPs (34,35). Atherosclerotic plaques also contain high levels of monocytederived TF + MPs (36), and cholesterol enrichment of human monocytic cells has been shown to induce the release of TF + MPs (37). These data suggest that TF expression by circulating monocytes and the release of TF + MPs may contribute to the systemic procoagulant state associated with hypercholesterolemia.…”

Section: Introductionmentioning

confidence: 94%

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.

160

138

View full text Add to dashboard Cite

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.

show abstract

“…Many chemical and physical stimuli, such as cytokines, unesterified cholesterol [6] , thrombin, endotoxins, tobacco smoke extract [7] , hypoxia, and shear stress [8] have been reported to trigger cellular MV release in studies from our group and other groups. All of the above-mentioned stimuli and factors are potentially involved in the development of diabetic vascular complications.…”

Section: General Characteristics Of Mvsmentioning

confidence: 99%

“…The procoagulant effects of MVs are mainly due to the exposure of negatively charged PS [37] and tissue factor (TF) [2,6,7,37,38] , which are involved in the coagulation cascade. The negatively charged membrane lipid PS enhances clot propagation.…”

Section: Mvs and Thrombosismentioning

confidence: 99%

“…Jansen et al showed that the decreased miR-126 in MVs may be responsible for the reduced endothelial repair in patients with CAD and diabetes [90] . We recently reported that cholesterol enrichment of human monocytes/macrophages induces the generation of TF + MVs with high procoagulant activity, which may contribute to prothrombotic conditions and atherothrombosis in hypercholesterolemia [6] . In addition, exposure to tobacco smoke substantially increases cardiovascular risk.…”

Section: Mvs In Diabetic Macrovascular Complicationsmentioning

confidence: 99%

See 1 more Smart Citation

Microvesicles and diabetic complications — novel mediators, potential biomarkers and therapeutic targets

2014

Self Cite

View full text Add to dashboard Cite

Cholesterol Enrichment of Human Monocyte/Macrophages Induces Surface Exposure of Phosphatidylserine and the Release of Biologically-Active Tissue Factor–Positive Microvesicles

Cited by 109 publications

References 59 publications

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

Granulocytes do not express but acquire monocyte-derived tissue factor in whole blood: evidence for a direct transfer

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

Microvesicles and diabetic complications — novel mediators, potential biomarkers and therapeutic targets

Contact Info

Product

Resources

About