Bench-to-bedside review: Circulating microparticles - a new player in sepsis?

In sepsis, inflammation and thrombosis are both the cause and the result of interactions between circulating (for example, leukocytes and platelets), endothelial and smooth muscle cells. Microparticles are proinflammatory and procoagulant fragments originating from plasma membrane generated after cellular activation and released in body fluids. In the vessel, they constitute a pool of bioactive effectors pulled from diverse cellular origins and may act as intercellular messengers. Microparticles expose phosphatidylserine, a procoagulant phospholipid made accessible after membrane remodelling, and tissue factor, the initiator of blood coagulation at the endothelial and leukocyte surface. They constitute a secretion pathway for IL-1β and up-regulate the proinflammatory response of target cells. Microparticles circulate at low levels in healthy individuals, but undergo phenotypic and quantitative changes that could play a pathophysiological role in inflammatory diseases. Microparticles may participate in the pathogenesis of sepsis through multiple ways. They are able to regulate vascular tone and are potent vascular proinflammatory and procoagulant mediators. Microparticles' abilities are of increasing interest in deciphering the mechanisms underlying the multiple organ dysfunction of septic shock

169 Does atrial differences in endothelium damage, leukocyte and platelet activation contribute to chamber specific thrombogenic status in patients with atrial fibrillation?

BackgroundIn atrial fibrillation (AF), the reasons why most of the thrombi form in the left atrium are mainly unknown. In the vasculature, endothelial damage together with platelet activation and inflammation contribute to initiation of blood coagulation and thrombus growth.ObjectiveThe purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation occur in patients with AF.MethodsTwenty patients (15 men, 5 women; age 55±8 years, 15 paroxystic AF, 5 persistent AF) with AF undergoing ablation were investigated. Blood samples from the left and right atrium were obtained at the start of the procedure. Procoagulant microparticles (MPs), reliable markers of vascular damage were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase assay and their cellular origin were determined (endothelium, platelet, leukocyte). In addition, platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet Pselectin (CD62P), active glycoprotein IIbIIIa receptor (PAC-1). Platelet aggregation was evaluated using Arachidonic acid (AA), ADP, TRAP and collageninduced whole blood aggregometry.ResultsNo atrial-specific differences in the levels of total procoagulant MP, leukocyte-derived-MP and platelet-derived MP could be evidenced. Conversely, endothelial-derived MPs (CD105+) were slightly elevated in the right atrium (RA 0.96±0.53 vs. LA 0.80±0.45nm PhtdSer Eq.; p=0.041). Likewise, collagen-induced platelet aggregation was evidenced in the right atrium (Collagen 1mg/l RA: 48±33% vs LA 37±29%; p 0.035; collagen 2,5mg/l RA: 76±25% vs LA: 60±29%; p=0.001).ConclusionsIn patients with AF, endothelial damage and collageninduced platelet aggregation appear slightly more pronounced in the right atrium. Our data did not substantiate the view that chamber specific enhanced thrombogenic status could be a reliable explanation for the increased propensity for thrombus formation observed in the left atrium in AF patients

Increased levels of circulating microparticles in primary Sjögren's syndrome, systemic lupus erythematosus and rheumatoid arthritis and relation with disease activity

INTRODUCTION: Cell stimulation leads to the shedding of phosphatidylserine (PS)-rich microparticles (MPs). Because autoimmune diseases (AIDs) are characterized by cell activation, we investigated level of circulating MPs as a possible biomarker in primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). METHODS: We measured plasma levels of total, platelet and leukocyte MPs by prothrombinase capture assay and flow cytometry in 43 patients with pSS, 20 with SLE and 24 with RA and in 44 healthy controls (HCs). Secretory phospholipase A2 (sPLA2) activity was assessed by fluorometry. Soluble CD40 ligand (sCD40L) and soluble P-selectin (sCD62P), reflecting platelet activation, were measured by ELISA. RESULTS: Patients with pSS showed increased plasma level of total MPs (mean +/- SEM 8.49 +/- 1.14 nM PS equivalent (Eq), P < 0.0001), as did patients with RA (7.23 +/- 1.05 n PS Eq, P = 0.004) and SLE (7.3 +/- 1.25 nM PS Eq, P = 0.0004), as compared with HCs (4.13 +/- 0.2 nM PS Eq). Patients with AIDs all showed increased level of platelet MPs (P < 0.0001), but only those with pSS showed increased level of leukocyte MPs (P < 0.0001). Results by capture assay and flow cytometry were correlated. In patients with high disease activity according to extra-glandular complications (pSS), DAS28 (RA) or SLEDAI (SLE) compared with low-activity patients, the MP level was only slightly increased in comparison with those having a low disease activity. Platelet MP level was inversely correlated with anti-DNA antibody level in SLE (r = -0.65; P = 0.003) and serum beta2 microglobulin level in pSS (r = -0.37; P < 0.03). The levels of total and platelet MPs were inversely correlated with sPLA2 activity (r = -0.37, P = 0.0007; r = -0.36, P = 0.002, respectively). sCD40L and sCD62P concentrations were significantly higher in pSS than in HC (P </= 0.006). CONCLUSIONS: Plasma MP level is elevated in pSS, as well as in SLE and RA, and could be used as a biomarker reflecting systemic cell activation. Level of leukocyte-derived MPs is increased in pSS only. The MP level is low in case of more severe AID, probably because of high secretory phospholipase A2 (sPLA2) activity, which leads to consumption of MPs. Increase of platelet-derived MPs, sCD40L and sCD62P, highlights platelet activation in pSS

Angiotensin {II}-induced redox-sensitive {SGLT}1 and 2 expression promotes high glucose-induced endothelial cell senescence

High glucose (HG)-induced endothelial senescence and dysfunction contribute to the increased cardiovascular risk in diabetes. Empagliflozin, a selective sodium glucose co-transporter2 (SGLT2) inhibitor, reduced the risk of cardiovascular mortality in type 2 diabetic patients but the protective mechanism remains unclear. This study examines the role of SGLT2 in HG-induced endothelial senescence and dysfunction. Porcine coronary artery cultured endothelial cells (ECs) or segments were exposed to HG (25 mmol/L) before determination of senescence-associated beta-galactosidase activity, protein level by Western blot and immunofluorescence staining, mRNA by RT-PCR, nitric oxide (NO) by electron paramagnetic resonance, oxidative stress using dihydroethidium and glucose uptake using 2-NBD-glucose. HG increased ECs senescence markers and oxidative stress, down-regulated eNOS expression and NO formation, and induced the expression of VCAM-1, tissue factor, and the local angiotensin system, all these effects were prevented by empagliflozin. Empagliflozin and LX-4211 (dual SGLT1/2 inhibitor) reduced glucose uptake stimulated by HG and H2O2 in ECs. HG increased SGLT1 and 2 protein levels in cultured ECs and native endothelium. Inhibition of the angiotensin system prevented HG-induced ECs senescence and SGLT1 and 2 expression. Thus, HG-induced ECs ageing is driven by the local angiotensin system via the redox-sensitive up-regulation of SGLT1 and 2, and, in turn, enhanced glucotoxicity

Microvesicles in vascular homeostasis and diseases. Position Paper of the European Society of Cardiology (ESC) Working Group on Atherosclerosis and Vascular Biology

Microvesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as "microparticles". There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research

Approche methodologique de role des proteines adhesives et de la coagulation dans les processus d'hemostase et d'angiogenese

SIGLEINIST T 77487 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Génération de microparticules procoagulantes dans le compartiment vasculaire

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF