Endothelial and antithrombotic actions of HDL

Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9063, USA.
Circulation Research (Impact Factor: 11.02). 07/2006; 98(11):1352-64. DOI: 10.1161/01.RES.0000225982.01988.93
Source: PubMed


It is well recognized that high-density lipoprotein (HDL)-cholesterol is antiatherogenic and serves a role in mediating cholesterol efflux from cells. However, HDL has multiple additional endothelial and antithrombotic actions that may also afford cardiovascular protection. HDL promotes the production of the atheroprotective signaling molecule nitric oxide (NO) by upregulating endothelial NO synthase (eNOS) expression, by maintaining the lipid environment in caveolae where eNOS is colocalized with partner signaling molecules, and by stimulating eNOS as a result of kinase cascade activation by the high-affinity HDL receptor scavenger receptor class B type I (SR-BI). HDL also protects endothelial cells from apoptosis and promotes their growth and their migration via SR-BI-initiated signaling. As importantly, there is evidence of a variety of mechanisms by which HDL is antithrombotic and thereby protective against arterial and venous thrombosis, including through the activation of prostacyclin synthesis. The antithrombotic properties may also be related to the abilities of HDL to attenuate the expression of tissue factor and selectins, to downregulate thrombin generation via the protein C pathway, and to directly and indirectly blunt platelet activation. Thus, in addition to its cholesterol-transporting properties, HDL favorably regulates endothelial cell phenotype and reduces the risk of thrombosis. With further investigation and resulting greater depth of understanding, these mechanisms may be harnessed to provide new prophylactic and therapeutic strategies to combat atherosclerosis and thrombotic disorders.

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Available from: John Griffin, Sep 23, 2015
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    • "There is, however accumulating evidence [37] that HDL has anti-thrombotic activity, involving in part an impact on coagulation. "
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    ABSTRACT: Purpose: Characterising high density lipoprotein (HDL) particles and their relevance to HDL function is a major research objective. One aim is to identify functionally distinct particles. To try to limit both functional and compositional heterogeneity the present study focused on paraoxonase-1 (PON1) as a target for isolation of a minor HDL subfraction. Experimental design: Immunoaffinity techniques were applied to isolate PON1-containing HDL (P-HDL) and total HDL (T-HDL), which were subsequently characterised and compared. Results: Analyses of the lipidomes showed significant differences between the fractions in the relative concentrations of individual lipid subspecies, notably reduced levels of unsaturated lysophosphatidylcholine (p<0.05) in P-HDL (reflected in a significantly reduced total lysophosphatidylcholine polyunsaturated fatty acid content, p<0.004). Significant differences were also observed for the proteomes. P-HDL was highly enriched in the anti-coagulant, vitamin K activated protein S (prot S) (p<0.0001) and alpha2 macroglobulin (p<0.01), compared to T-HDL. Conversely, pro-coagulant proteins kininogen 1 and histidine-rich glycoprotein were largely excluded from P-HDL. Immunoabsorption of PON1 from plasma significantly reduced prot S anti-coagulant activity. Conclusions and clinical relevance: The P-HDL lipidome and proteome showed significant differences from T-HDL. Enrichment in anti-coagulation proteins indicates complementary functionalities within P-HDL particles and underlines their anti-atherosclerotic potential. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 09/2015; DOI:10.1002/prca.201500062 · 2.96 Impact Factor
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    • "A few clinical studies have reported that circulating levels of platelet MVs (Nomura et al., 2009) and tissue factor-positive MVs from T cells or neutrophils (Diamant et al., 2002) negatively correlate with plasma HDL levels. HDL may also exert a protective role on endothelial function by enhancing eNOS expression and NO release (Terasaka et al., 2010) and by indirectly inhibiting apoptosis (Mineo et al., 2006) and generation of MVs (Diamant et al., 2002; Nomura et al., 2009). Still, MVs produced by stimulated cells can also preserve normal endothelial function. "
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    ABSTRACT: Extracellular vesicles released by most cell types, include apoptotic bodies (ABs), microvesicles (MVs) and exosomes. They play a crucial role in physiology and pathology, contributing to "cell-to-cell" communication by modifying the phenotype and the function of target cells. Thus, extracellular vesicles participate in the key processes of atherosclerosis from endothelial dysfunction, vascular wall inflammation to vascular remodeling. The purpose of this review is to summarize recent findings on extracellular vesicle formation, structure, release and clearance. We focus on the deleterious and beneficial effects of extracellular vesicles in the development of atherosclerosis. The potential role of extracellular vesicles as biomarkers and pharmacological targets, their innate therapeutic capacity, or their use for novel drug delivery devices in atherosclerotic cardiovascular diseases will also be discussed. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 06/2015; 763(Pt A). DOI:10.1016/j.ejphar.2015.06.047 · 2.53 Impact Factor
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    • "Reduced HDL was identified in patients presenting with massive PE (Wang et al., 2010) and was associated with VTE recurrence (Eichinger et al., 2007). Possible HDL-related protective mechanisms include reduced thrombin generation via promotion of the protein C pathway (Griffin et al., 1999), enhanced endothelial nitric oxide synthase activity and reduced leukocyte adhesion to endothelium (Mineo et al., 2006). In our patients with schizophrenia, raised hsCRP and triglycerides were independent predictors of impaired OCP and OHP supporting a role for inflammation and the metabolic syndrome. "
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    ABSTRACT: Patients with schizophrenia are at increased risk of venous thromboembolism. The mechanisms underlying this association are poorly understood. We investigated whether there is a global hypercoagulable state in patients with schizophrenia utilising the overall haemostatic potential (OHP) assay which assesses overall coagulation potential (OCP), haemostatic potential (OHP) and fibrinolytic potential (OFP). Citrated plasma was collected for OHP assays from patients with schizophrenia on long-term antipsychotic treatment and compared with healthy age- and sex-matched controls. Time courses of fibrin formation and degradation were measured by spectrophotometry (absorption of 405nm) after the addition of tissue factor and tissue plasminogen activator to plasma. Ninety patients with schizophrenia (antipsychotic treatment-15.9±9.7years) and 30 controls were recruited. Patients with schizophrenia had higher rates of smoking and levels of inflammatory markers (high-sensitivity C-reactive protein and neutrophil-to-lymphocyte ratio) than controls. Whilst D-dimer, fibrinogen and platelet count did not differ between patients with schizophrenia and controls, the OCP (54.0±12.6 vs 45.9±9.1, p=0.002) and OHP (12.6±5.8 vs 7.2±3.7, p<0.001) were higher, and OFP was lower (76.6±9.8% vs 84.9±6.4%, p<0.001) in patients with schizophrenia, implying both a hypercoagulable and hypofibrinolytic state in these patients. Importantly, abnormalities in overall coagulation were independently predicted by levels of plasminogen-activator-inhibitor-1, fibrinogen, platelet count, inflammatory markers and plasma triglycerides, suggesting a multifactorial aetiology. Patients with schizophrenia have evidence of a global hypercoagulable and hypofibrinolytic state which may contribute to their increased risk of venous thromboembolism. Copyright © 2015 Elsevier B.V. All rights reserved.
    Schizophrenia Research 01/2015; 162(1-3). DOI:10.1016/j.schres.2014.12.042 · 3.92 Impact Factor
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