Anionic Phospholipids Lose Their Procoagulant Properties When Incorporated into High Density Lipoproteins

Oslakovic, Cecilia; Krisinger, Michael J.; Andersson, Astra; Jauhiainen, Matti; Ehnholm, Christian; Dahlbäck, Björn

doi:10.1074/jbc.m807286200

Cited by 57 publications

(60 citation statements)

References 46 publications

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“…137, 138 Other modes of action that could explain the beneficial effects of HDLs on coagulation include a reduction in platelet-activating factor production by endothelial cells, 139 inhibition of thrombin-induced endothelial tissue factor expression, 140 suppression of the procoagulant activity of erythrocytes, 141 and inactivation of anionic phospholipids that are required to accommodate the prothrombinase complex. 142 Consistent with these findings proposing a protective function of HDLs against thrombosis, Naqvi et al observed an independent inverse correlation between HDL-C levels and ex vivo thrombus formation in humans. 143 Furthermore, flow-induced thrombus formation was diminished by reconstituted HDLs as determined by flow-chamber based assays.…”

Section: Anti-inflammatory Effectssupporting

confidence: 59%

High-Density Lipoproteins

Annema

Eckardstein

2013

Circ J

142

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Low plasma levels of high-density lipoprotein (HDL) cholesterol are associated with increased risks of coronary artery disease (CAD). HDL particles exert many effects in vitro and in vivo that may protect arteries from chemical or biological harm or facilitate repair of injuries. Nevertheless, HDL has not yet been successfully exploited for therapy. One potential reason for this shortfall is the structural and functional complexity of HDL particles, which carry more than 80 different proteins and more than 200 lipid species as well as several microRNAs and other potentially bioactive molecules. This physiological heterogeneity is further increased in several inflammatory conditions that increase cardiovascular risk, including CAD itself but also diabetes mellitus, chronic kidney disease, and rheumatic diseases. The quantitative and qualitative modifications of the proteome and lipidome, as well as the resulting loss of functions or gain of dysfunctions, are not recovered by the biomarker HDL-cholesterol. As yet the relative importance of the many physiological and pathological activities of normal and dysfunctional HDL, respectively, for the pathogenesis of atherosclerosis is unknown. The answer to this question, as well as detailed knowledge of structure-function-relationships of HDL-associated molecules, is a prerequisite to exploit HDL for the development of anti-atherogenic drugs as well as of diagnostic biomarkers for the identification, personalized treatment stratification, and monitoring of patients at increased cardiovascular risk. 2433Multifunctional but Vulnerable HDL munication of results. 15 As yet, clinical and epidemiological studies have come to discrepant and inconsistent conclusions on the prognostic performance of HDL subclasses differentiated by size. 14,20-24 Sometimes the associations of cardiovascular risk with the various HDL subclass concentrations were not stronger than with HDL-C, 20,21 and even if so, the associations with size were discrepant: significant associations with risk of cardiovascular events or stroke were found for small HDL in some studies, 22,23 but for medium-sized HDL 21,23 or large HDL 14,20,21,24 in others.Previous proteomic, lipidomic, and transcriptomic studies revealed a much greater structural complexity of HDLs: 80 different proteins, 25,26 more than 200 lipid species, 27,28 and several microRNAs 29,30 have been identified in HDL isolated from plasma by either ultracentrifugation, gel filtration, or immunoaffinity chromatography (Figure 1). Among the proteins, apoA-II is present in HDLs at the highest concentration after that of apoA-I and has been investigated for its cardiovascular risk association by several studies. In contrast to initial findings, large prospective studies did not find any significant differences in the risk association between apoA-II-containing and apoA-II-free HDL. [15][16][17] Despite their much lower concentrations relative to the 2 major proteins apoA-I and apoA-II and relative to the major lipids, many quantitatively minor componen...

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Section: Anti-inflammatory Effectssupporting

confidence: 59%

High-Density Lipoproteins

Annema

Eckardstein

2013

Circ J

142

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“…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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“…In addition, the expression of hApoA-I in apoE defi cient mice and in hApo(a)-transgenic mice yielded similar results (89)(90)(91). A reduction of atherosclerosis has been reproduced in various apoA-I gene thereby abolishing their pro-coagulant properties (70). Whether these anti-thrombotic effects apply to humans is unknown.…”

Section: Apoa-imentioning

confidence: 99%

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

Vergeer

Holleboom

Kastelein

et al. 2010

Journal of Lipid Research

199

122

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This article is available online at http://www.jlr.org the imagination. Because of a general consensus that HDL protects against atherosclerosis, what we shall term the HDL hypothesis, strategies have been developed to raise plasma HDL levels or to improve HDL function. However, it is increasingly questioned whether such interventions will indeed reduce the risk of atherosclerosis. This review summarizes the reported evidence that supports the HDL hypothesis. EPIDEMIOLOGYA low plasma HDL-C concentration is among the strongest, statistically independent risk factors for cardiovascular disease (CVD) (2). In a widely cited meta-analysis of four large studies (total number of individuals studied: 15,252), a 1 mg/dl increase of HDL-C levels was reported to be associated with a 2-3% decreased CVD risk (3). This result provides an epidemiological argument in favor of therapeutically raising HDL-C levels. One may draw parallels with the detrimental consequences of elevated lowdensity lipoprotein cholesterol (LDL-C) levels and blood pressure, which have been successfully controlled through therapy, resulting in signifi cant reductions of cardiovascular mortality and morbidity (4, 5) . It should be noted, however, that the associations between elevated LDL-C and blood pressure and increased CVD risk refl ect causal relationships, whereas such a relation between low HDL-C levels and increased CVD is not undisputed (6, 7). This is related to the fact that HDL-C levels are infl uenced by many different variables that also affect CVD risk: 1 ) Men have on average lower HDL-C levels than women (8). (1) reported that plasma levels of high-density lipoprotein cholesterol (HDL-C) were reduced in patients with coronary artery disease. In 1977, Gordon et al. (2) subsequently showed that low HDL-C is a risk factor for coronary heart disease in the Framingham study. These important fi ndings have given rise to a large number of diverse HDL studies over the last few decades. The numerous different and apparently unrelated beneficial effects that have since been ascribed to HDL appeal to

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Anionic Phospholipids Lose Their Procoagulant Properties When Incorporated into High Density Lipoproteins

Cited by 57 publications

References 46 publications

High-Density Lipoproteins

High-Density Lipoproteins

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

The HDL hypothesis: does high-density lipoprotein protect from atherosclerosis?

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