Reconstituted High-Density Lipoprotein Inhibits Thrombin-Induced Endothelial Tissue Factor Expression Through Inhibition of RhoA and Stimulation of Phosphatidylinositol 3-Kinase but not Akt/Endothelial Nitric Oxide Synthase

Viswambharan, Hema; Ming, Xiu‐Fen; Zhu, Shengsi; Hubsch, Alphonse; Lerch, P.; Vergères, Guy; Rusconi, Sandro; Yang, Zhihong

doi:10.1161/01.res.0000124302.20396.b7

Cited by 94 publications

(83 citation statements)

References 60 publications

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“…In the presence of HDL platelet activation and aggregation are significantly inhibited, 32-34 which may in turn lead to reduced thrombus formation. 32 Other proposed mechanisms by which HDL may reduce the risk of atherothrombosis are increased activities of the anticoagulants activated protein C and protein S, 35 reduced synthesis of plateletactiving factor and tissue factor by endothelial cells, 36,37 and neutralization of procoagulatory anionic phospholipids. 38 …”

Section: Hdl and Protection Against Cardiovascular Diseasementioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary heart disease. HDL mediates cholesterol efflux from macrophages for reverse transport to the liver and elicits many anti-inflammatory and anti-oxidative activities which are potentially antiatherogenic. Nevertheless, HDL has not been successfully targeted by drugs for prevention or treatment of cardiovascular diseases. One potential reason is the targeting of HDL cholesterol which does not capture the structural and functional complexity of HDL particles. Hundreds of lipid species and dozens of proteins as well as several microRNAs have been identified in HDL. This physiological heterogeneity is further increased in pathologic conditions due to additional quantitative and qualitative molecular changes of HDL components which have been associated with both loss of physiological function and gain of pathologic dysfunction. This structural and functional complexity of HDL has prevented clear assignments of molecules to the functions of normal HDL and dysfunctions of pathologic HDL. Systematic analyses of structure-function relationships of HDL-associated molecules and their modifications are needed to test the different components and functions of HDL for their relative contribution in the pathogenesis of atherosclerosis. The derived biomarkers and targets may eventually help to exploit HDL for treatment and diagnostics of cardiovascular diseases.

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Section: Hdl and Protection Against Cardiovascular Diseasementioning

confidence: 99%

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Annema

Eckardstein

2016

Translational Research

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“…Inhibition of the catalytic activity of the tissue factor-factor VIIA complex by HDLs has been shown to impede the activation of the procoagulant factor X (Carson 1981). Besides direct inactivation of tissue factor and factor Va, HDLs are able to modulate the tissue factor-activated coagulation cascade by downregulating tissue factor expression in thrombin-stimulated endothelial cells through suppression of RhoA and induction of PI3K (Viswambharan et al 2004). In addition, incorporation of anionic phospholipids into apoA-I-containing rHDL particles resulted in the loss of their procoagulant properties, revealing that, by scavenging anionic phospholipids, apoA-I may control blood coagulation (Oslakovic et al 2009).…”

Section: Hdls and Coagulationmentioning

confidence: 99%

HDL and Atherothrombotic Vascular Disease

Annema

Eckardstein

Kovanen

2014

High Density Lipoproteins

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High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.

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“…PI3Ks are important negative regulators of TF expression in human endothelial cells (16,17); and this pathway suppresses inflammation and coagulation in endotoxaemic mice (18). Targeting PI3K activity in various inflammatory conditions has become an active area of investigation (19,20).…”

Section: Introductionmentioning

confidence: 99%

Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition

Gebhard¹,

Holy²,

Camici³

et al. 2012

Thromb Haemost

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SummaryTissue factor (TF) is the key activator of coagulation and is involved in acute coronary syndromes. Caffeine is often reported to increase cardiovascular risk; however, its effect on cardiovascular morbidity and mortality is controversial. Hence, this study was designed to investigate the impact of caffeine on endothelial TF expression in vitro. Caffeine concentration-dependently enhanced TF protein expression and surface activity in human endothelial cells stimulated by tumour necrosis factor (TNF)-α or thrombin. Caffeine inhibited phosphatidylinositol 3-kinase (PI3K) activity and this effect was comparable to that of the known PI3K inhibitor LY294002. Consistently, treatment of endothelial cells with LY294002 enhanced TNF-α induced TF expression to a similar extent as caffeine, and adenoviral expression of the active PI3K mutant (p110) reversed the effect of both caffeine and LY294002 on TF expression. Caffeine and LY294002 increased DNA binding capacity of the transcription factor nuclear factor κB, whereas the activation pattern of mitogen-activated protein kinases (MAPK) remained unaltered. Luciferase reporter assay revealed a caffeine dependent activation of the TF promoter, and RT-PCR revealed a dose dependent increase in TF mRNA levels when stimulated with caffeine in the presence of TNF-α. In conclusion, caffeine enhances TNF-α-induced endothelial TF protein expression as well as surface activity by inhibition of PI3K signalling. Since the caffeine concentrations applied in the present study are within the plasma range measured in humans, our findings indicate that caffeine enhances the prothrombotic potential of endothelial cells and underscore the importance of PI3K in mediating these effects.

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Reconstituted High-Density Lipoprotein Inhibits Thrombin-Induced Endothelial Tissue Factor Expression Through Inhibition of RhoA and Stimulation of Phosphatidylinositol 3-Kinase but not Akt/Endothelial Nitric Oxide Synthase

Cited by 94 publications

References 60 publications

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

HDL and Atherothrombotic Vascular Disease

Caffeine induces endothelial tissue factor expression via phosphatidylinositol 3-kinase inhibition

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