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See detailTumor microenvironment affects the composition of endothelial-derived exosomes: impact in tumor progression
Njock, Makon-Sébastien ULiege; O'Grady, Tina ULiege; Nivelles, Olivier ULiege et al

Conference (2018, September 13)

The tumor microenvironment plays a crucial role in the progression of tumor growth and metastasis by deregulating various physiological processes including angiogenesis and inflammation. Several studies ... [more ▼]

The tumor microenvironment plays a crucial role in the progression of tumor growth and metastasis by deregulating various physiological processes including angiogenesis and inflammation. Several studies have previously demonstrated that tumor-derived exosomes are actively involved in the mediation of tumorigenesis by “reprogramming” target cells (e.g. endothelial cells (ECs)) through transfer of pro-angiogenic microRNAs. But the function of exosomes released by target cells is poorly studied. Consequently, we sought to determine the composition of exosomes released by ECs under tumor microenvironment, and to assess whether these vesicles present different functional properties. Using RNA-seq approaches, we demonstrated that exosomes released by ECs in tumor microenvironment context present a specific repertory of microRNAs associated to tumor angiogenesis and inflammatory pathways. Furthermore, we showed that these vesicles were able to optimize inflammatory response of immune cells by transferring several dysregulated microRNAs. Currently, we are identifying the molecular pathways modulated by endothelial-derived exosomes in tumor microenvironment. [less ▲]

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See detailIntegrating long and short sequencing data for a global overview of the endothelial extracellular vesicle RNA landscape
O'Grady, Tina ULiege; Njock, Makon-Sébastien ULiege; Lion, Michelle ULiege et al

Poster (2018, May)

Background: Although extracellular vesicles (EVs) are well known to be enriched in miRNAs and other short RNA species, long RNA transcripts such as mRNA and lncRNA have been reported by several groups. We ... [more ▼]

Background: Although extracellular vesicles (EVs) are well known to be enriched in miRNAs and other short RNA species, long RNA transcripts such as mRNA and lncRNA have been reported by several groups. We use RNA-Seq analysis in conjunction with wet bench techniques to provide a global analysis of the RNA content of endothelial cell EVs. Methods: EVs from primary human umbilical vein endothelial cell (HUVEC) cultures were isolated by sequential ultracentrifugation and immunocapture. RNA was extracted from cells and EVs, then short and long RNA libraries were prepared and sequenced. Reads were mapped to the human genome and transcriptome and mapped reads were analysed to determine transcript type and differential abundance between cells and EVs. RT-PCR was used to investigate integrity of long RNA transcripts. Gene ontology analyses were performed to determine enrichment of functional terms. Results: RNA in primary endothelial EVs is highly diverse in terms of length, type and abundance. As expected, endothelial EV RNA content is dominated by short RNA molecules, in particular snRNA and piRNA. Additionally, long rRNA, mRNA and lncRNA transcripts are present. Many of these transcripts are intact, putatively functional transcripts and are detectable at robust levels. Analysis of differential abundance between EVs and cells reveals significant differences in miRNA, snRNA, piRNA, mRNA and lncRNA profiles. LncRNAs in particular show a striking distribution, with about 13 times more lncRNA transcripts being enriched in EVs than in cells. Few of these lncRNAs have been fully functionally characterized, but gene ontology analysis of EV-enriched mRNA transcripts reveals an overabundance of genes coding for ribosomal proteins, elongation factors and other translation-related proteins. Summary/conclusion: Endothelial EVs are enriched for short and long regulatory RNA with the potential to control gene expression at both transcriptional and post-transcriptional levels. [less ▲]

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See detailSputum exosomes - promising biomarkers for idiopathic pulmonary fibrosis
Njock, Makon-Sébastien ULiege; GUIOT, Julien ULiege; HENKET, Monique ULiege et al

Poster (2018, May)

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown etiology which leads rapidly to death. As diagnosis of IPF is complex, the development of ... [more ▼]

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown etiology which leads rapidly to death. As diagnosis of IPF is complex, the development of novel molecular biomarkers is a central challenge for the future of translational research. Consequently, we sought to characterize microRNA (miR) content of exosomes from sputum of IPF patients compared to healthy donors in order to identify novel biomarkers of the disease. Methods: Exosomes were isolated from induced sputum samples of 14 IPF patients diagnosed following American Thoracic Society (ATS) /European Respiratory Society (ERS) recommendations and 11 healthy donors with standard ultracentrifugation protocol. Exosomal miR content was analysed by miR qPCR arrays, and diseases/biological processes associated to altered miRs were determined by bioinformatic analysis. Results: The presence of exosomes was confirmed in sputum from both IPF patients and healthy donors. The profiling of exosomal miRs revealed 21 differentially expressed miRs in the sputum of IPF patients compared to healthy donors. Further validation of miRs presenting an aberrant expression allowed us to identify for the first time an IPF-specific miR signature from sputum exosomes, among which miR-142-3p and miR-33a-5p present an upregulation (fold change (FC)>3, p < 0.01), whereas let-7d-5p a downregulation (FC < 0.5, p < 0.01). The bioinformatic analysis revealed that altered miRs are associated to inflammatory diseases, among which IPF is the most relevant one (p = 3.78E-10). Interestingly, most of the biological processes highlighted in this analysis are in agreement with IPF etiology, which confers to our candidates an evident role as IPF biomarkers. Based on these findings, functional tests with IPF-sputum exosomes and mimics of altered miRs are underway to test their impact on IPF progression. Summary/Conclusion: For the first time, we identified potential biomarkers for IPF from sputum exosomes. Our findings may thus lead to a better understanding about the roles of these miRs in the pathogenesis of IPF and thus open new avenues for therapeutic approaches. This study reinforced the concept that sputum exosomes might be a novel source of biomarkers for the diagnosis of pulmonary diseases. [less ▲]

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See detailSputum exosomes: promising biomarkers for idiopathic pulmonary fibrosis.
Njock, Makon-Sébastien ULiege; GUIOT, Julien ULiege; HENKET, Monique ULiege et al

in Thorax (2018)

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology which leads rapidly to death. As diagnosis of IPF is complex, we aimed to characterise ... [more ▼]

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease of unknown aetiology which leads rapidly to death. As diagnosis of IPF is complex, we aimed to characterise microRNA (miRNA) content of exosomes from sputum of patients with IPF. Using miRNA quantitative PCR array, we found a substantial dysregulation of sputum exosomal miRNA levels between patients with IPF and healthy subjects and identified a unique signature of three miRNAs. Interestingly, we found a negative correlation between miR-142-3p and diffusing capacity of the lungs for carbon monoxide/alveolar volume. This is the first characterisation of miRNA content of sputum-derived exosomes in IPF that identified promising biomarkers for diagnosis and disease severity. [less ▲]

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See detailCirculating Extracellular Vesicles From Mouse and Rat Models of Diabetes Reveal Specific Microrna Signatures as Biomarkers of Diabetic Cardiomyopathy
Chandy, Mark; Njock, Makon-Sébastien ULiege; Veitch, Shawn et al

Poster (2017, November 14)

Background: Type-2 diabetes (T2D) is associated with both reduced and preserved ejection fraction heart failure. Obese db/db mice and Goto Kakizaki (GK) rats represents animals models of T2D that develop ... [more ▼]

Background: Type-2 diabetes (T2D) is associated with both reduced and preserved ejection fraction heart failure. Obese db/db mice and Goto Kakizaki (GK) rats represents animals models of T2D that develop cardiac dysfunction similar to human diabetic cardiomyopathy, in which dominant early findings are of diastolic (and not systolic) dysfunction. Circulating extracellular vesicles (EV) contain microRNAs (miR) that can be transferred to recipient cells to modulate their function. We explored whether analysis of EV content from animals models of T2D would inform on the pathophysiology, diagnosis and therapeutic targets of cardiac dysfunction. Hypothesis: EV from animal models of T2D will have altered miR content that contributes to the pathophysiology of diabetic cardiomyopathy. Methods & Results: miR qPCR arrays on circulating EV isolated from plasma of db/db mice reveal several miR (-7, -15, -25, -30e, -148a, -150, -195) modulated during disease progression. These changes in miR content occur prior to echocardiographic evidence of diastolic dysfunction, including global longitudinal strain and strain rate. Among circulating EV miR from the GK rat model, miR-30 was also upregulated (1.42 fold, p=0.03) compared to Wistar rat. In GK rat left ventricle, and in H9C2 rat cardiac myoblast cultured in 25 mM high glucose media, mass spectrometry revealed proteins that were overexpressed in the diabetic heart including oxidative phosphorylation, glycolysis, fatty acid degredation and the citrate cycle. Using a bioinformatics approach, we next identified metabolic pathways affected by miR-30. Based on these findings, in vivo therapy with antagomiR and mimics of miR-30 are underway to test causality and reversibility of the observed cardiomyopathy. Conclusion: EV from animal models of T2D have altered miR content, including miR-30. We also identify alterations in the expression of a network of metabolism genes in the heart, which are implicated in diabetic cardiomyopathy. If causality is supported by experiments that enhance or block miR-30 expression in these models of disease, we will have identified a novel biomarker and therapeutic target for diabetic cardiomyopathy. [less ▲]

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See detailDynamic regulation of VEGF-inducible genes by an ERK/ERG/p300 transcriptional network.
Fish, Jason E.; Cantu Gutierrez, Manuel; Dang, Lan T. et al

in Development (2017), 144(13), 2428-2444

The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for ... [more ▼]

The transcriptional pathways activated downstream of vascular endothelial growth factor (VEGF) signaling during angiogenesis remain incompletely characterized. By assessing the signals responsible for induction of the Notch ligand delta-like 4 (DLL4) in endothelial cells, we find that activation of the MAPK/ERK pathway mirrors the rapid and dynamic induction of DLL4 transcription and that this pathway is required for DLL4 expression. Furthermore, VEGF/ERK signaling induces phosphorylation and activation of the ETS transcription factor ERG, a prerequisite for DLL4 induction. Transcription of DLL4 coincides with dynamic ERG-dependent recruitment of the transcriptional co-activator p300. Genome-wide gene expression profiling identified a network of VEGF-responsive and ERG-dependent genes, and ERG chromatin immunoprecipitation (ChIP)-seq revealed the presence of conserved ERG-bound putative enhancer elements near these target genes. Functional experiments performed in vitro and in vivo confirm that this network of genes requires ERK, ERG and p300 activity. Finally, genome-editing and transgenic approaches demonstrate that a highly conserved ERG-bound enhancer located upstream of HLX (which encodes a transcription factor implicated in sprouting angiogenesis) is required for its VEGF-mediated induction. Collectively, these findings elucidate a novel transcriptional pathway contributing to VEGF-dependent angiogenesis. [less ▲]

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See detailTumour microenvironment affects the composition of endothelial cell-derived extracellular vesicles: impact in tumour progression
Njock, Makon-Sébastien ULiege; O’Grady, christina; Dequiedt, Franck et al

in Journal of Extracellular Vesicles (2017, May 15)

The tumor microenvironment plays a crucial role in the progression of tumor growth and metastasis by deregulating various physiological processes including angiogenesis and inflammation. Several studies ... [more ▼]

The tumor microenvironment plays a crucial role in the progression of tumor growth and metastasis by deregulating various physiological processes including angiogenesis and inflammation. Several studies have previously demonstrated that tumor-derived extracellular vesicles (EVs) are actively involved in the mediation of tumorigenesis by “reprogramming” target cells (e.g. endothelial cells (ECs)) through transfer of pro-angiogenic microRNAs. But the function of EVs released by target cells is poorly studied. Consequently, we sought to determine the composition of EVs released by ECs under tumor microenvironment, and to assess whether these vesicles present different functional properties. Using RNA-seq approaches, we demonstrated that EVs released by ECs in tumor microenvironment context present a specific repertory of microRNAs associated to tumor angiogenesis and inflammatory pathways. Interestingly, some of the dysregulated microRNAs are differently expressed at the cellular and exosomal levels. Furthermore, we showed that these vesicles were able to deregulate angiogenesis pathway by transferring several dysregulated microRNAs to target cells. Currently, we are identifying the molecular targets and pathways modulated by EC-derived EVs under tumor microenvironment. [less ▲]

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See detailDiabetes affects extracellular vesicle content and function
Njock, Makon-Sébastien ULiege; Chandy, Mark; Veitch, Shawn C. et al

in Journal of Extracellular Vesicles (2017, May 15)

Introduction: The role of circulating extracellular vesicles in cardiovascular diseases remains incompletely understood.We previously demonstrated that extracellular vesicles circulating in plasma of ... [more ▼]

Introduction: The role of circulating extracellular vesicles in cardiovascular diseases remains incompletely understood.We previously demonstrated that extracellular vesicles circulating in plasma of healthy mice can suppress monocyte activation through transfer of anti-inflammatory microRNAs. Here we set out to determine the effect of diabetes on the function of plasma extracellular vesicles since diabetes is known to negatively affect vascular function, playing a contributory role in cardiovascular diseases. Methods: Circulating plasma extracellular vesicles were isolated from mouse and rat models of type 2 diabetes. Extracellular vesicles were characterised with nanoparticle tracking analysis. Furthermore, qPCR and RNA-sequencing approaches were used to characterise vesicle content and function. Results: We found that vesicle abundance and size were increased in mouse and rat models of type 2 diabetes. MicroRNAs in plasma extracellular vesicles were dysregulated during the progression of diabetes in thesemodels. Finally, we demonstrate that vesicles isolated from diabetic plasma can activate inflammatory pathways in endothelial cells. Current studies are seeking to determine the contribution of microRNA transfer to endothelial dysfunction. Conclusions: These studies suggest that the microRNA content and function of extracellular vesicles are dysregulated during diabetes. Advancements in this area could facilitate the development of more effective non-invasive diagnostics, prognostics, and therapeutics. Funding: Supported by funding from the Canadian Vascular Network and the Canadian Institutes of Health Research. [less ▲]

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See detailEndothelial miRNAs as Cellular Messengers in Cardiometabolic Diseases.
Njock, Makon-Sébastien ULiege; Fish, Jason E.

in Trends in endocrinology and metabolism: TEM (2017), 28(3), 237-246

Metabolic syndrome is a clustering of risk factors that increases susceptibility to serious cardiometabolic complications, including type 2 diabetes (T2D) and myocardial infarction. Understanding the ... [more ▼]

Metabolic syndrome is a clustering of risk factors that increases susceptibility to serious cardiometabolic complications, including type 2 diabetes (T2D) and myocardial infarction. Understanding the underlying mechanisms will advance the development of diagnostic and therapeutic approaches. A prominent feature of cardiometabolic diseases is endothelial dysfunction. Endothelial cell (EC) homeostasis and response to pathological stimuli are controlled by gene regulatory networks in which miRNAs play a critical role. Recently, miRNAs have been implicated as cell-cell messengers that can influence cellular function. This review investigates the known and potential roles for miRNA-based cell-cell communication in the control of cardiovascular health and explores the value of identifying miRNA biomarkers and developing therapeutics that harness or antagonize miRNA-based communication. [less ▲]

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See detailmiR-155 Modifies Inflammation, Endothelial Activation and Blood-Brain Barrier Dysfunction in Cerebral Malaria.
Barker, Kevin Richard; Lu, Ziyue; Kim, Hani et al

in Molecular medicine (Cambridge, Mass.) (2017), 23

miR-155 has been shown to participate in host response to infection and neuro-inflammation via negative regulation of blood-brain-barrier (BBB) integrity and T cell function. We hypothesized that miR-155 ... [more ▼]

miR-155 has been shown to participate in host response to infection and neuro-inflammation via negative regulation of blood-brain-barrier (BBB) integrity and T cell function. We hypothesized that miR-155 may contribute to the pathogenesis of cerebral malaria (CM). To test this hypothesis, we used a genetic approach to modulate miR-155 expression in an experimental model of cerebral malaria (ECM). In addition, an engineered endothelialized microvessel system and serum samples from Ugandan children with CM were used to examine an anti-miR-155 as a potential adjunctive therapeutic for severe malaria. Despite higher parasitemia, survival was significantly improved in miR-155(-/-) mice vs. wild-type littermate mice in ECM. Improved survival was associated with preservation of BBB integrity and reduced endothelial activation, despite increased levels of pro-inflammatory cytokines. Pre-treatment with antagomir-155 reduced vascular leak induced by human CM sera in an ex vivo endothelial microvessel model. These data provide evidence supporting a mechanistic role for miR-155 in host response to malaria via regulation of endothelial activation, microvascular leak and BBB dysfunction in CM. [less ▲]

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See detailEndothelial cells suppress monocyte activation through secretion of extracellular vesicles containing antiinflammatory microRNAs.
Njock, Makon-Sébastien ULiege; Cheng, Henry S.; Dang, Lan T. et al

in Blood (2015), 125(20), 3202-12

The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the ... [more ▼]

The blood contains high concentrations of circulating extracellular vesicles (EVs), and their levels and contents are altered in several disease states, including cardiovascular disease. However, the function of circulating EVs, especially the microRNAs (miRNAs) that they contain, are poorly understood. We sought to determine the effect of secreted vesicles produced by quiescent endothelial cells (ECs) on monocyte inflammatory responses and to assess whether transfer of microRNAs occurs between these cells. We observed that monocytic cells cocultured (but not in contact) with ECs were refractory to inflammatory activation. Further characterization revealed that endothelium-derived EVs (EC-EVs) suppressed monocyte activation by enhancing immunomodulatory responses and diminishing proinflammatory responses. EVs isolated from mouse plasma also suppressed monocyte activation. Importantly, injection of EC-EVs in vivo repressed monocyte/macrophage activation, confirming our in vitro findings. We found that several antiinflammatory microRNAs were elevated in EC-EV-treated monocytes. In particular, miR-10a was transferred to monocytic cells from EC-EVs and could repress inflammatory signaling through the targeting of several components of the NF-kappaB pathway, including IRAK4. Our findings reveal that ECs secrete EVs that can modulate monocyte activation and suggest that altered EV secretion and/or microRNA content may affect vascular inflammation in the setting of cardiovascular disease. [less ▲]

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See detailNoncoding RNAs regulate NF-kappaB signaling to modulate blood vessel inflammation.
Cheng, Henry S.; Njock, Makon-Sébastien ULiege; Khyzha, Nadiya et al

in Frontiers in Genetics (2014), 5

Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke ... [more ▼]

Cardiovascular diseases such as atherosclerosis are one of the leading causes of morbidity and mortality worldwide. The clinical manifestations of atherosclerosis, which include heart attack and stroke, occur several decades after initiation of the disease and become more severe with age. Inflammation of blood vessels plays a prominent role in atherogenesis. Activation of the endothelium by inflammatory mediators leads to the recruitment of circulating inflammatory cells, which drives atherosclerotic plaque formation and progression. Inflammatory signaling within the endothelium is driven predominantly by the pro-inflammatory transcription factor, NF-kappaB. Interestingly, activation of NF-kappaB is enhanced during the normal aging process and this may contribute to the development of cardiovascular disease. Importantly, studies utilizing mouse models of vascular inflammation and atherosclerosis are uncovering a network of noncoding RNAs, particularly microRNAs, which impinge on the NF-kappaB signaling pathway. Here we summarize the literature regarding the control of vascular inflammation by microRNAs, and provide insight into how these microRNA-based pathways might be harnessed for therapeutic treatment of disease. We also discuss emerging areas of endothelial cell biology, including the involvement of long noncoding RNAs and circulating microRNAs in the control of vascular inflammation. [less ▲]

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See detailLycopene modulates THP1 and Caco2 cells inflammatory state through transcriptional and nontranscriptional processes.
Njock, Makon-Sébastien ULiege; Fouchier, Francis; Seree, Eric et al

in Mediators of Inflammation (2014), 2014

We revisited the action of a carotenoid, the lycopene, on the expression of proinflammatory genes, reactive oxygen species (ROS) production, and metalloprotease (MMP9) activity. THP1 and Caco2 cell lines ... [more ▼]

We revisited the action of a carotenoid, the lycopene, on the expression of proinflammatory genes, reactive oxygen species (ROS) production, and metalloprotease (MMP9) activity. THP1 and Caco2 cell lines were used as in vitro models for the two main cell types found in intestine tissue, that is, monocytes and epithelial cells. Proinflammatory condition was induced using either phorbol ester acetate (PMA), lipopolysaccharide (LPS) or tumor necrosis factor (TNF). In THP1 cells, short term pretreatment (2 h) with a low concentration (2 muM) of lycopene reinforce proinflammatory gene expression. The extent of the effect of lycopene is dependent on the proinflammtory stimulus (PMA, LPS or TNF) used. Lycopene enhanced MMP9 secretion via a c-AMP-dependent process, and reduced ROS production at higher concentrations than 2 muM. Cell culture media, conditioned by PMA-treated monocytes and then transferred on CaCo-2 epithelial cells, induced a proinflammatory state in these cells. The extent of this inflammatory effect was reduced when cells has been pretreated (12 h) with lycopene. At low concentration (2 muM or less), lycopene appeared to promote an inflammatory state not correlated with ROS modulation. At higher concentration (5 muM-20 muM), an anti-inflammatory effect takes place as a decrease of ROS production was detected. So, both concentration and time have to be considered in order to define the exact issue of the effect of carotenoids present in meals. [less ▲]

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See detailSecreted miRNAs regulate vascular inflammation.
Njock, Makon-Sébastien ULiege

Scientific conference (2014)

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See detailLeukocyte- and endothelial-derived microparticles: a circulating source for fibrinolysis.
Lacroix, Romaric; Plawinski, Laurent; Robert, Stephane et al

in Haematologica (2012), 97(12), 1864-72

BACKGROUND: We recently assigned a new fibrinolytic function to cell-derived microparticles in vitro. In this study we explored the relevance of this novel property of microparticles to the in vivo ... [more ▼]

BACKGROUND: We recently assigned a new fibrinolytic function to cell-derived microparticles in vitro. In this study we explored the relevance of this novel property of microparticles to the in vivo situation. DESIGN AND METHODS: Circulating microparticles were isolated from the plasma of patients with thrombotic thrombocytopenic purpura or cardiovascular disease and from healthy subjects. Microparticles were also obtained from purified human blood cell subpopulations. The plasminogen activators on microparticles were identified by flow cytometry and enzyme-linked immunosorbent assays; their capacity to generate plasmin was quantified with a chromogenic assay and their fibrinolytic activity was determined by zymography. RESULTS: Circulating microparticles isolated from patients generate a range of plasmin activity at their surface. This property was related to a variable content of urokinase-type plasminogen activator and/or tissue plasminogen activator. Using distinct microparticle subpopulations, we demonstrated that plasmin is generated on endothelial and leukocyte microparticles, but not on microparticles of platelet or erythrocyte origin. Leukocyte-derived microparticles bear urokinase-type plasminogen activator and its receptor whereas endothelial microparticles carry tissue plasminogen activator and tissue plasminogen activator/inhibitor complexes. CONCLUSIONS: Endothelial and leukocyte microparticles, bearing respectively tissue plasminogen activator or urokinase-type plasminogen activator, support a part of the fibrinolytic activity in the circulation which is modulated in pathological settings. Awareness of this blood-borne fibrinolytic activity conveyed by microparticles provides a more comprehensive view of the role of microparticles in the hemostatic equilibrium. [less ▲]

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See detailC0082 Circulating leukocyte- and endothelial-derived microparticles support a fibrinolytic activity
Lacroix, Romaric; Plawinski, Laurent; Doeuvre, Loïc et al

in Thrombosis Research (2012, October), 130

Background: Microparticles (MPs) derived from activated platelets, leukocytes and endothelial cells are well known for their procoagulant activity. We recently assigned a new fibrinolytic function to ... [more ▼]

Background: Microparticles (MPs) derived from activated platelets, leukocytes and endothelial cells are well known for their procoagulant activity. We recently assigned a new fibrinolytic function to endothelial derived MPs in vitro. However, the relevance of this novel propertyto the in vivo situation remains unclear. Methods: Circulating MPs were isolated from plasma of thrombotic thrombocytopenic purpura or cardiovascular disease patients and from healthy subjects. MPswere also obtained from purified human blood cell subpopulations. Identification of plasminogen activators on MPs was performed by zymography and their capacity to generate plasmin by chromogenic assay. Results: Circulating MPs isolated from patientsgenerate a range of plasmin activity at their surface. This property was related to a variable content in uPA and/or tPA. Using distinct MP subpopulations derived from endothelial cells, platelets, leukocytes and erythrocytes, we demonstrated that plasmin is generated on endothelial- and leukocytederived MPs, but is absent on MPs from platelet or erythrocyte origins. Leukocyte-derived MPs bear uPA and its receptor uPAR whereas endothelial-derived MPs carry tPA and tPA/inhibitor complexes. Comment: Endothelial- and leukocyte-derived MPs, bearing respectively tPA or uPA, support at least a part of fibrinolytic activity in the circulation that is modulated in pathological settings. This blood-borne fibrinolytic activity conveyed by MPs provides a more comprehensive view on the role of MPs in the haemostatic equilibrium and put forward the basis for a potential new biomarker. [less ▲]

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See detailEndothelial-derived microparticles: Biological conveyors at the crossroad of inflammation, thrombosis and angiogenesis
Leroyer, Aurélie S.; Anfosso, Francine; Lacroix, Romaric et al

in Thrombosis and Haemostasis (2010), 104(3), 456-63

Endothelial microparticles (EMP) are complex vesicular structures that can be shed by activated or apoptotic endothelial cells. EMP are composed of a phospholipid bilayer that exposes transmembrane ... [more ▼]

Endothelial microparticles (EMP) are complex vesicular structures that can be shed by activated or apoptotic endothelial cells. EMP are composed of a phospholipid bilayer that exposes transmembrane proteins and receptors and encloses cytosolic components such as enzymes, transcription factors and mRNA derived from their parent cells. Thus, EMP behave as biological conveyors playing a key role in the tuning of vascular homeostasis. This review focuses on the multifaceted roles of EMP, notably in coagulation, inflammation and angiogenesis and also on the mechanisms that trigger their formation. In this context, EMP could compromise vascular homeostasis and then represent key players in the pathogenesis of several inflammatory and thrombotic diseases. Consequently, elucidating their role and their mechanisms of formation will bring new insights into the understanding of endothelial-associated diseases. Moreover, in the future, it can open novel therapeutic perspectives based on the inhibition of EMP release. [less ▲]

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See detailTRAIL/Apo2L mediates the release of procoagulant endothelial microparticles induced by thrombin in vitro: a potential mechanism linking inflammation and coagulation.
Simoncini, Stephanie; Njock, Makon-Sébastien ULiege; Robert, Stephane et al

in Circulation Research (2009), 104(8), 943-51

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are ... [more ▼]

Microparticles are small vesicles playing a crucial role in cell communication by promoting prothrombotic and proinflammatory responses. However, the molecular mechanisms underlying their release are still elusive. We previously established that thrombin promoted the generation of endothelial microparticles (EMPs). In the present study, gene profiling identified TRAIL/Apo2L, a cytokine belonging to the tumor necrosis factor-alpha superfamily, as a target of thrombin. Thrombin increased the expression of cell-associated and soluble forms of TRAIL (sTRAIL) in HMEC-1 cells and human umbilical vein endothelial cells (HUVECs). Blocking TRAIL by specific antibodies or by small interfering RNA reduced both the number and the procoagulant activity of EMPs released by thrombin. Consistent with an involvement of sTRAIL in thrombin-induced EMP release, we showed that (1) exogenously added sTRAIL generated procoagulant EMPs; (2) supernatants from thrombin-stimulated endothelial cells induced EMP release by HMEC-1 cells and HUVECs, whereas those recovered from TRAIL knockdown endothelial cells displayed no effect. TRAIL/TRAIL-R2 complex mediated EMP release by initiating the recruitment of adaptor proteins and the activation of nuclear factor kappaB. Moreover, sTRAIL modulated intercellular adhesion molecule-1 and interleukin-8 expression induced by thrombin by a downstream pathway involving nuclear factor kappaB activation. Our data reveal a novel mechanism controlling EMP release and identify TRAIL as a key partner in the pathway linking coagulation and inflammation elicited by thrombin. [less ▲]

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