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Biomedical subjects

J-M Freyssinet

Publications and source records attributed to J-M Freyssinet.

9 recordsLinked to original sources
PubMed2006

[Microparticles during sepsis and trauma. A link between inflammation and thrombotic processes].

Sepsis and trauma lead to a sustained activation of monocytes and endothelium. In the vascular compartment, stimulated cells release microparticles. Circulating MP provide an additional procoagulant phospholipid surface enabling the assembly of the clotting enzymes complexes and thrombin generation. Their procoagulant properties rely on the exposition of phosphatidylserine, made accessible after cell stimulation and on the possible presence of tissue factor, the main cellular initiator of blood coagulation. Microparticles constitute the main reservoir of blood-borne tissue factor activity. At sites of endothelium injury, enhanced release or recruitment of procoagulant MP through P-selectin-PSGL-1 pathway could concentrate TF activity above a threshold allowing blood coagulation to be triggered. Converging evidences from experimental or clinical data highlight a role for MP harboring tissue factor in the initiation of disseminated intravascular coagulopathy. In these settings, the pharmacological modulation of MP levels or biological functions through activated protein C or factor VIIa allows challenging issues.

Apoptosis↗
PubMed2006

Cyclic GMP modulates store-operated calcium entry inducing phosphatidylserine translocation at the surface of megakaryocytic cells.

When subjected to stimulation, cells from the vascular compartment show a spontaneous collapse of the plasma membrane phospholipid asymmetry and phosphatidylserine is exposed at the external leaflet. Thus, phosphatidylserine externalization is essential for normal hemostasis and phagocytosis. The mechanism governing the migration of phosphatidylserine to the exoplasmic leaflet is not yet fully understood. We have proposed that store-operated calcium entry (SOCE) constitutes a key step of this process. Here, interaction of [Ca(2+)](i), cAMP and cGMP pathways and phosphatidylserine exposure was examined in human megakaryocytic cells. The membrane permeable cAMP and cGMP analogues, pCPT-cAMP and pCPT-cGMP, enhanced the Ca(2+) signal induced by ionophore and SOCE. Responses to pCPT-cAMP and pCPT-cGMP were independent of protein kinase A, protein kinase G (PKG) or ERK pathways. Inhibition of small G-proteins reduced or abolished the increase of [Ca(2+)](i) induced by pCPT-cAMP or pCPT-cGMP, respectively. pCPT-cGMP but not pCPT-cAMP enhanced the ability of cells to expose phosphatidylserine. This effect was not prevented by the inhibition of PKG or small G-proteins. These results show the differential role of cyclic nucleotides in the Ca(2+)-dependent membrane remodeling. Hence, pCPT-cGMP is another regulatory element for the completion of SOCE-induced phosphatidylserine transmembrane redistribution in HEL cells through a mechanism implicating small G-proteins.

Biological Transport↗
PubMed2006

Origin and biological significance of shed-membrane microparticles.

Microparticles (MPs) are small vesicles released from the membrane surface during eukaryotic cell activation or apoptosis. They originate from various cell types, displaying the typical surface cell proteins and cytoplasmic components of their cell origin. Their procoagulant properties are linked to phosphatidylserine exposed at their surface. Numerous reports have shown that MPs are able to mediate long-range signaling, acting on different targets from those of their own cellular origin. MPs-mediated binding to other cells occurs by integration into the membrane, by adhesion to the cell surface or by ligand-receptor interaction. Elevated levels of circulating MPs have been detected in cardiovascular and immune-mediated diseases. Despite extensive studies of the procoagulant and pro-inflammatory properties of MPs, little is known about their effect on vascular function. MPs accumulate in atherosclerotic plaques and injured vascular wall. Circulating MPs from patients with myocardial infarction induce endothelial dysfunction by impairing the endothelial nitric oxide (NO) pathway, without causing changes in endothelial NO-synthase (eNOS) expression. However, MPs from T-cells may induce endothelial dysfunction, altering gene expression of eNOS and caveolin-1. Moreover, MPs may promote the expression of pro-inflammatory proteins implicated in vascular contractility alterations. This review describes the origin of MPs and their biological role in physiological conditions and in various pathological states, with special reference to the possible linkage between their pro-inflammatory and procoagulant properties and vascular dysfunction.

Animals↗
PubMed2004

Modulation of signal transduction through the cellular prion protein is linked to its incorporation in lipid rafts.

Because expressed at a significant level at the membrane of human T cells, we made the hypothesis that the cellular prion protein (PrPc) could behave as a receptor, and be responsible for signal transduction. PrPc engagement by specific antibodies was observed to induce an increase in cytosolic calcium concentration and led to enhanced activity of Src protein tyrosine kinases. Antibodies to CD4 and CD59 did not influence calcium fluxes or signaling. The effect was maximal after the formation of a network involving avidin and biotinylated antibody to PrPc and was inhibited after raft disruption. PrPc localization was not restricted to rafts in resting cells but engagement was a prerequisite for signaling induction, with concomitant PrPc recruitment into rafts. These results suggest a role for PrPc in signaling pathways, and show that lateral redistribution of the protein into rafts is important for subsequent signal transduction.

Antibodies, Monoclonal↗
PubMed2004

Rho A participates in the regulation of phosphatidylserine-dependent procoagulant activity at the surface of megakaryocytic cells.

Once exposed at the external surface of activated platelets or apoptotic cells, phosphatidylserine, an anionic phospholipid mostly sequestered in the inner leaflet of the plasma membrane, plays essential roles in hemostasis and phagocytosis. The mechanism governing the migration of the phosphatidylserine to the exoplasmic leaflet is not yet fully understood. We have proposed that store-operated calcium entry (SOCE) constitutes a key step of this process. ERK pathway is among the elements modulating SOCE and phosphatidylserine externalization in megakaryocytic HEL cells. Here, we investigated the role of small GTPase Rho A, which may interact with the ERK pathway. Specific inhibitors of Rho A (exoenzyme C3 and toxin B) reduced both SOCE and phosphatidylserine-dependent procoagulant activity. Simultaneous inhibition of Rho A and extracellular signal-regulated kinase (ERK) pathways did not elicit further reduction with respect to each individual one. Rho A can regulate SOCE and phosphatidylserine exposure through the reorganization of actin cytoskeleton, but not through ROCK pathway. Hence, Rho A is another regulatory element for the completion of SOCE-induced phosphatidylserine transmembrane redistribution in HEL cells.

Calcium↗
PubMed2004

Circulating procoagulant microparticles and soluble GPV in myocardial infarction treated by primary percutaneous transluminal coronary angioplasty. A possible role for GPIIb-IIIa antagonists.

Circulating procoagulant microparticles (MP) were measured as markers of vascular damage and prothrombotic risk in patients undergoing ST-segment myocardial infarction (STEMI) treated by primary percutaneous transluminal coronary angioplasty (PTCA) and additional GPIIb-IIIa antagonists. Cells possibly more responsive to GPIIb-IIIa (alpha(IIb)beta(3)) antagonists were evidenced through MP phenotypes by comparison with healthy volunteers (HV) and STEMI patients treated by PTCA without GPIIb-IIIa antagonist (CP). In 50 STEMI patients, blood samples were collected at day 1 and day 6. Circulating procoagulant MP were captured on annexin V and quantified by prothrombinase assay as nanomolar phosphatidylserine equivalents (nm PhtdSer). Platelet activation by thrombin was confirmed through independent measurement of soluble GPV (sGPV). With respect to HV, procoagulant MP levels were high in patients with STEMI or unstable angina, platelet-derived MP and elevated sGPV testifying to significant platelet activation. A substantial release of endothelial-derived MP was evidenced simultaneously. In abciximab-treated patients, procoagulant MP, mainly of platelet origin, decreased precociously at day 1 (4.2 +/- 0.6 vs. CP 15.5 +/- 2.1 nm PhtdSer; P = 0.001) together with sGPV (36 +/- 3 vs. CP 58 +/- 8 ng mL(-1); P = 0.02). Leukocyte-derived MP decreased at day 6 (0.12 +/- 0.04 vs. CP 0.56 +/- 0.12 nm PhtdSer; P = 0.01) suggesting a possible effect on underlying inflammatory status. In patients presenting cardiovascular events at 6-month follow-up, procoagulant MP levels at day 1 could be indicative of a worsened outcome. MP could constitute a relevant parameter for the follow-up of STEMI patients treated by GPIIb-IIIa antagonists.

Abciximab↗
PubMed2003

Protective effects of vitamin C on endothelium damage and platelet activation during myocardial infarction in patients with sustained generation of circulating microparticles.

During myocardial infarction (MI), high levels of circulating procoagulant microparticles (MP) shed from endothelial cells and platelets diffuse prothrombotic and proinflammatory potentials crucial for the coronary prognosis. In addition to conventional treatments, we evaluated whether vitamin C treatment could modify circulating levels of procoagulant MP. Upon admission, 61 patients with MI were prospectively randomized for immediate additional vitamin C treatment. Circulating MP were quantified by functional prothrombinase assay before and after 5 days of vitamin C administration (1 g day-1). The cellular origin of MP was also assessed. In vitamin C-treated patients, the reduction in platelet-derived MP was 10% higher (P = 0.01). In patients with diabetes mellitus, dyslipidemia or more than two cardiovascular risk factors, vitamin C decreased endothelial and platelet-derived MP levels by approximately 70% and 13%, respectively. This early effect on circulating platelet and endothelial-derived MP, testifies to the importance of oxidative stress during MI. Vitamin C could prove beneficial for the outcome of patients at higher thrombotic risk.

Acute Disease↗
PubMed2003

Cellular microparticles: what are they bad or good for?

Microparticles are fragments released from the plasma membrane of most stimulated or apoptotic cells. After having long been considered inert cell debris, of possible value for the diagnosis of cell activation or death, there is increasing documented evidence that they can interact with neighboring or remote cells, in which case they acquire a pathophysiologic potential. On the one hand, deleterious microparticles stemming from activated cells can elicit an adverse response from other cells, themselves undergoing membrane vesiculation, leading to pathogenic amplification. On the other hand, since they are thought to reflect a balance between cell stimulation, proliferation, and death, it is conceivable that they are discerned as sensors for the maintenance of homeostasis in multicellular organisms. Because vesiculation is an integral part of the plasma-membrane remodeling process, with the transverse migration of procoagulant phosphatidylserine from the cytoplasmic to the exoplasmic leaflet as the central event, the majority of released microparticles are thought to fulfill a hemostatic function under physiologic conditions. This is particularly true when they originate from platelets, with possible deviation towards thrombosis when produced in excess. Owing to these procoagulant properties, the hemostasis laboratory offers the most appropriate tools for the assessment of the in vivo significance of microparticles.

Animals↗