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Background: Evaluate the impact of the MiniMed™ 780G advanced hybrid closed-loop (AHCL) system on the glucose profile of pregnant women with type 1 diabetes (T1D) and maternal-neonatal complications. Methods: From April 2021 to September 2022, pregnant women with T1D treated with the AHCL system were included in an observational multicenter retrospective study. Continuous glucose monitoring parameters were analyzed monthly during pregnancy as well as maternal-neonatal complications. Results: Thirteen pregnant women, including a twin pregnancy (age: 33 ± 3 years, hemoglobin A1c [HbA1c]: 7.3% ± 0.7%, insulin doses: 0.72 ± 0.21 U/kg/day) were analyzed. At delivery, gestational age was 37 ± 2 weeks. During first 2 weeks of pregnancy, time in range (TIR, 63-140 mg/dL) was 46% (34-55) and increased to 54% (51-59) (P < 0.01), 64% (48-68) (P < 0.01), and 66% (60-70) (P < 0.001) during the first, second, and third trimester, respectively. During the night, TIR (63-140 mg/dL) was >70% throughout pregnancy. Time below the range <63 mg/dL increased from 0.5% (0-2) to 1.3% (0.7-2.2), 2% (1.2-3.5) (P < 0.05), and 1.3% (1.31-3) (P < 0.05) during the first, second, and third trimester, respectively. At delivery, insulin doses increased to 0.89 ± 0.35 IU/kg/day (P < 0.01), and HbA1c decreased to 6.4% ± 0.6% (P = 0.005). The reported carbohydrate amount increased from 167 ± 363 g/d during early pregnancy to 243 ± 106 g/d (P < 0.01) at delivery. The birthweight was 3134 ± 711 g, with 5/14 macrosomia and 2/14 neonatal hypoglycemia. Moreover, 5/13 patients had a preeclampsia and 9/13 a cesarean section, including three cases of scarred uterus. The Clinical Trial Registration number is: CE-2022-55. Conclusion: The AHCL system provided good glucose control during pregnancy and recommendation targets were reached during the nocturnal period only. The maternal and neonatal complications remained high.
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Diabetes Mellitus Tipo 1 , Gravidez em Diabéticas , Adulto , Feminino , Humanos , Recém-Nascido , Gravidez , Glicemia , Automonitorização da Glicemia , Cesárea , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucose , Hemoglobinas Glicadas , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Sistemas de Infusão de Insulina/efeitos adversos , Gravidez em Diabéticas/tratamento farmacológico , Gestantes , Estudos RetrospectivosRESUMO
Aim: To investigate the impact of teleconsultation on glycemic control in patients with diabetes during the COVID-19 pandemic. Methods: In this observational prospective study, the main outcome was the comparison of glycated hemoglobin (HbA1c) between patients with or without teleconsultation at 6-month follow-up. Results: From March 17 to May 31, 2020, 610 patients were included, 456 were followed-up using Teleconsultation présent (TC+) and 154 not using No Teleconsultation (TC-). Patients of TC+ Group were younger, 57 ± 17 versus 65 ± 15.5 years (p < 0.001), with a lower body mass index, 28 ± 6.2 kg/m2 versus 30 ± 5.8 kg/m2, compared to those of TC- Group (p < 0.001). HbA1c were comparable between the two groups: 7.35 ± 0.27% for TC+ versus 7.48 ± 0.22% for TC- Group. At 6-month follow-up, HbA1c was lower in TC+ versus TC- Group: 7.21 ± 0.15% versus 7.6 ± 0.18% (p = 0.004). Conclusion: Our findings point toward the feasibility and usefulness of teleconsultation for the follow-up of patients with diabetes in such exceptional circumstances.
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COVID-19 , Diabetes Mellitus , Consulta Remota , Telemedicina , Humanos , COVID-19/epidemiologia , Estudos Prospectivos , Hemoglobinas Glicadas , Pandemias , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/terapiaRESUMO
Objective: Evaluate the efficacy of a new modality of insulin therapy associating both the sensor-augmented pump therapy with predictive low-glucose management (SAP-PLGM) and a telemedicine follow-up in patients with Type 1 diabetes (T1D) in a real-life setting. Methods: T1D adults under Minimed 640G system with a telemedicine follow-up for glucose management were included in a retrospective study. The primary endpoint was HbA1c while continuous glucose monitoring parameters (CGM) and treatment compliance were the secondary endpoints. These parameters were analyzed according to the therapeutic indication, HbA1c ≥ 8 % (Group A) or severe hypoglycemic events (Group B) and in patients switched to SAP-PLGM therapy. Results: 62 patients were analyzed with a 28 ± 12 months of follow-up. In Group A, HbA1c decreased from 8.3 ± 0.4 % to 7.7 ± 0.7 % (p < 0.05) and to 7.9 ± 0.3 % (p < 0.05) after 2 and 3 years, respectively. In patients switched to SAP-PLGM therapy, HbA1c decreased from 7.7 ± 0.7 % to 7.2 ± 0.8 % (p < 0.05) at 2 years. After 6 months, the time-below-range (<70 mg/dL) decreased from 2.1 % [0.6-4] to 1.1 % [0.3-2.6] (p < 0.05). Severe hypoglycemic events decreased from 1.62 to 0.5 events/patient/year in Group B (p < 0.05). At 3 years, treatment compliance was 92 % [70-97] in the total population. Conclusions: Long-term real-life treatment with the SAP-PLGM therapy combined with telemedicine was associated with improved glycemic control in T1D, along with high treatment compliance.
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BACKGROUND: Hospitalization of persons with diabetes in an inpatient diabetes unit is challenging, notably for patients having different profiles. We aimed to evaluate the feasibility and the benefit of a continuous glucose monitoring (CGM) telemetry system to control glucose excursions in hospitalized patients with diabetes, according to their diabetes type and the reasons for their hospitalization. METHOD: A prospective pilot study was conducted in 53 insulin-requiring diabetes patients hospitalized in the general ward. Glucose was monitored using Guardian Connect (GC, Medtronic) to adopt insulin therapy. The time in range (TIR, target 70-180 mg/dL), the time below range (TBR), and the time above range (TAR) were recorded by GC between the start of hospitalization (SH) and end of hospitalization (EH), and analyzed according to the diabetes type (type 1 diabetes n = 28, type 2 diabetes n = 25) and the reasons for hospitalization (acute complications n = 35, therapeutic education n = 18). Patient and caregiver satisfaction was also assessed. RESULTS: In patients with type 2 diabetes and those hospitalized for acute complications, TIR significantly increased between the SH and EH, from 75.7% (95%CI 48.5-84.6) to 82.2% (95%CI 63.2-91.8) P = 0.043 and from 58.3% (95%CI 46.3-69.7) to 66.4% (95%CI 55.6-75.5) P = 0.031, respectively, and TAR significantly decreased, with no change in TBR. In patients with diabetes hospitalized for therapeutic education, TBR significantly decreased from 3.4% (95%CI 0-9.4) to 0% (95%CI 0-3.8) P = 0.037. Finally, 94% of patients and caregivers deemed the GC system useful. CONCLUSIONS: CGM telemetry system use is feasible and well accepted in patients hospitalized in diabetes care unit and could be useful to improve therapeutic education and metabolic control, especially for specific homogenous populations with diabetes.
Assuntos
Automonitorização da Glicemia , Diabetes Mellitus Tipo 2 , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Estudos de Viabilidade , Humanos , Pacientes Internados , Insulina/uso terapêutico , Projetos Piloto , Estudos Prospectivos , TelemetriaRESUMO
BACKGROUND: Ischemia-driven islet isolation procedure is one of the limiting causes of pancreatic islet transplantation. Ischemia-reperfusion process is associated with endothelium dysfunction and the release of pro-senescent microvesicles. We investigated whether pro-senescent endothelial microvesicles prompt islet senescence and dysfunction in vitro. MATERIAL AND METHODS: Pancreatic islets were isolated from male young rats. Replicative endothelial senescence was induced by serial passaging of primary porcine coronary artery endothelial cells, and microvesicles were isolated either from young passage 1 (P1) or senescent passage 3 (P3) endothelial cells. Islet viability was assessed by fluorescence microscopy, apoptosis by flow cytometry, and Western blot. Function was assessed by insulin secretion and islet senescence markers p53, p21, and p16 by Western blot. Microvesicles were stained by the PKH26 lipid fluorescent probe and their islet integration assessed by microscopy and flow cytometry. RESULTS: Regardless of the passage, half microvesicles were integrated in target islets after 24 hours incubation. Insulin secretion significantly decreased after treatment by senescent microvesicles (P3: 1.7 ± 0.2 vs untreated islet: 2.7 ± 0.2, P < .05) without altering the islet viability (89.47% ± 1.69 vs 93.15% ± 0.97) and with no significant apoptosis. Senescent microvesicles significantly doubled the expression of p53, p21, and p16 (P < .05), whereas young microvesicles had no significant effect. CONCLUSION: Pro-senescent endothelial microvesicles specifically accelerate the senescence of islets and alter their function. These data suggest that islet isolation contributes to endothelial driven islet senescence.
Assuntos
Micropartículas Derivadas de Células/metabolismo , Senescência Celular , Ilhotas Pancreáticas/metabolismo , Animais , Apoptose/genética , Sobrevivência Celular , Micropartículas Derivadas de Células/fisiologia , Células Cultivadas , Senescência Celular/genética , Vasos Coronários/citologia , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Glucose/farmacologia , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Suínos , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismoRESUMO
Endothelial senescence is an emerging cause of vascular dysfunction. Because microparticles are effectors of endothelial inflammation and vascular injury after ischaemia-reperfusion, we examined leucocyte-derived microparticles of spleen origin as possible contributors. Microparticles were generated from primary rat splenocytes by either lipopolysaccharide or phorbol-myristate-acetate/calcium ionophore, under conditions mimicking innate and adaptive immune responses. Incubation of primary porcine coronary endothelial cells with either type of microparticles, but not with those from unstimulated splenocytes, leads to a similar threefold raise in senescence-associated ß-galactosidase activity within 48 hours, indicating accelerated senescence, to endothelial oxidative stress, and a fivefold and threefold increase in p21 and p16 senescence markers after 24 hours. After 12-hour incubation, the endothelial-dependent relaxation of coronary artery rings was reduced by 50%, at distinct optimal microparticle concentration. In vitro, microparticles were pro-thrombotic by up-regulating the local angiotensin system, by prompting tissue factor activity and a secondary generation of pro-coagulant endothelial microparticles. They initiated an early pro-inflammatory response by inducing phosphorylation of NF-κB, MAP kinases and Akt after 1 hour, and up-regulated VCAM-1 and ICAM-1 at 24 hours. Accordingly, VCAM-1 and COX-2 were also up-regulated in the coronary artery endothelium and eNOS down-regulated. Lipopolysaccharide specifically favoured the shedding of neutrophil- and monocyte-derived microparticles. A 80% immuno-depletion of neutrophil microparticles reduced endothelial senescence by 55%, indicating a key role. Altogether, data suggest that microparticles from activated splenocytes prompt early pro-inflammatory, pro-coagulant and pro-senescent responses in endothelial cells through redox-sensitive pathways. The control of neutrophil shedding could preserve the endothelium at site of ischaemia-reperfusion-driven inflammation and delay its dysfunction.
Assuntos
Micropartículas Derivadas de Células/metabolismo , Senescência Celular , Células Endoteliais/patologia , Endotélio Vascular/fisiopatologia , Inflamação/patologia , Neutrófilos/metabolismo , Traumatismo por Reperfusão/fisiopatologia , Angiotensinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Coagulação Sanguínea/efeitos dos fármacos , Linhagem da Célula/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Lipopolissacarídeos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , NF-kappa B/metabolismo , Neutrófilos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Ratos Wistar , Baço/efeitos dos fármacos , Baço/patologia , Suínos , Acetato de Tetradecanoilforbol/farmacologia , Tromboplastina/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Omega-3 polyunsaturated fatty acids (PUFAs) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been shown to protect the cardiovascular system, in part, by stimulating the endothelial formation of nitric oxide (NO). EPA:DHA 6:1 has been identified as a potent omega 3 PUFA formulation to induce endothelium-dependent vasorelaxation and activation of endothelial NO synthase (eNOS). This study examined whether intake of EPA:DHA 6:1 (500 mg/kg/day) for 2 weeks improves an established endothelial dysfunction in old rats (20 months old), and, if so, the underlying mechanism was subsequently determined. In the main mesenteric artery rings, an endothelial dysfunction characterized by a blunted NO component, an abolished endothelium-dependent hyperpolarization component, and increased endothelium-dependent contractile responses (EDCFs) are observed in old rats compared to young rats. Age-related endothelial dysfunction was associated with increased vascular formation of reactive oxygen species (ROS) and expression of eNOS, components of the local angiotensin system, senescence markers, and cyclooxygenase-2 (COX-2), and the downregulation of COX-1. The EPA:DHA 6:1 treatment improved the NO-mediated relaxation, reduced the EDCF-dependent contractile response and the vascular formation of ROS, and normalized the expression level of all target proteins in the old arterial wall. Thus, the present findings indicate that a 2-week intake of EPA:DHA 6:1 by old rats restored endothelium-dependent NO-mediated relaxations, most likely, by preventing the upregulation of the local angiotensin system and the subsequent formation of ROS.
Assuntos
Endotélio Vascular/fisiologia , Ácidos Graxos Ômega-3/administração & dosagem , Artérias Mesentéricas/fisiologia , NADPH Oxidases/metabolismo , Peptidil Dipeptidase A/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Fatores Etários , Animais , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácidos Docosa-Hexaenoicos/química , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/química , Ácidos Graxos Ômega-3/química , Imunofluorescência , Masculino , Artérias Mesentéricas/efeitos dos fármacos , Artérias Mesentéricas/metabolismo , Ratos Wistar , Proteína Supressora de Tumor p53/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
Markers of early pancreatic islet graft dysfunction and its causes are lacking. We monitored 19 type 1 diabetes islet-transplanted patients for up to 36 months following last islet injection. Patients were categorized as Partial (PS) or complete (S) Success, or Graft Failure (F), using the ß-score as an indicator of graft function. F was the subset reference of maximum worsened graft outcome. To identify the immune, pancreatic, and liver contribution to the graft dysfunction, the cell origin and concentration of circulating microvesicles (MVs) were assessed, including MVs from insulin-secreting ß-cells typified by polysialic acid of neural cell adhesion molecule (PSA-NCAM), and data were compared with values of the ß-score. Similar ranges of PSA-NCAM+ -MVs were found in healthy volunteers and S patients, indicating minimal cell damage. In PS, a 2-fold elevation in PSA-NCAM+ -MVs preceded each ß-score drop along with a concomitant rise in insulin needs, suggesting ß-cell damage or altered function. Significant elevation of liver asialoglycoprotein receptor (ASGPR)+ -MVs, endothelial CD105+ -MVs, neutrophil CD66b+ -MVs, monocyte CD 14+ -MVs, and T4 lymphocyte CD4+ -MVs occurred before each ß-score drop, CD8+ -MVs increased only in F, and B lymphocyte CD19+ -MVs remained undetectable. In conclusion, PSA-NCAM+ -MVs are noninvasive early markers of transplant dysfunction, while ASGPR+ -MVs signal host tissue remodeling. Leukocyte MVs could identify the cause of graft dysfunction.
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Micropartículas Derivadas de Células/patologia , Diabetes Mellitus Tipo 1/terapia , Rejeição de Enxerto/diagnóstico , Células Secretoras de Insulina/patologia , Transplante das Ilhotas Pancreáticas/efeitos adversos , Leucócitos/patologia , Complicações Pós-Operatórias/diagnóstico , Adulto , Idoso , Feminino , Seguimentos , Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Complicações Pós-Operatórias/etiologia , Prognóstico , Fatores de RiscoRESUMO
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 H2 O2 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.
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Angiotensina II/farmacologia , Senescência Celular/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Glucose/metabolismo , Oxirredução/efeitos dos fármacos , Transportador 1 de Glucose-Sódio/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo , Envelhecimento/efeitos dos fármacos , Envelhecimento/metabolismo , Animais , Compostos Benzidrílicos/farmacologia , Células Cultivadas , Regulação para Baixo/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Glucosídeos/farmacologia , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , SuínosRESUMO
Islet transplantation is associated with early ischaemia/reperfusion, localized coagulation and redox-sensitive endothelial dysfunction. In animal models, islet cytoprotection by activated protein C (aPC) restores islet vascularization and protects graft function, suggesting that aPC triggers various lineages. aPC also prompts the release of endothelial MP that bear EPCR, its specific receptor. Microparticles (MP) are plasma membrane procoagulant vesicles, surrogate markers of stress and cellular effectors. We measured the cytoprotective effects of aPC on endothelial and insulin-secreting Rin-m5f ß-cells and its role in autocrine and paracrine MP-mediated cell crosstalk under conditions of oxidative stress. MP from aPC-treated primary endothelial (EC) or ß-cells were applied to H2 O2 -treated Rin-m5f. aPC activity was measured by enzymatic assay and ROS species by dihydroethidium. The capture of PKH26-stained MP and the expression of EPCR were probed by fluorescence microscopy and apoptosis by flow cytometry. aPC treatment enhanced both annexin A1 (ANXA1) and PAR-1 expression in EC and to a lesser extent in ß-cells. MP from aPC-treated EC (eMaPC ) exhibited high EPCR and annexin A1 content, protected ß-cells, restored insulin secretion and were captured by 80% of ß cells in a phosphatidylserine and ANXA1-dependent mechanism. eMP activated EPCR/PAR-1 and ANXA1/FPR2-dependent pathways and up-regulated the expression of EPCR, and of FPR2/ALX, the ANXA1 receptor. Cytoprotection was confirmed in H2 O2 -treated rat islets with increased viability (62% versus 48% H2 O2 ), reduced apoptosis and preserved insulin secretion in response to glucose elevation (16 versus 5 ng/ml insulin per 10 islets). MP may prove a promising therapeutic tool in the protection of transplanted islets.
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Anexina A1/genética , Micropartículas Derivadas de Células/química , Células Secretoras de Insulina/efeitos dos fármacos , Proteína C/farmacologia , Proteínas Serina-Treonina Quinases/genética , Receptores de Endotelina/genética , Receptores de Lipoxinas/genética , Animais , Anexina A1/metabolismo , Linhagem Celular , Micropartículas Derivadas de Células/metabolismo , Vasos Coronários/química , Vasos Coronários/citologia , Vasos Coronários/metabolismo , Células Endoteliais/química , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Regulação da Expressão Gênica , Peróxido de Hidrogênio/antagonistas & inibidores , Peróxido de Hidrogênio/farmacologia , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/citologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Cultura Primária de Células , Substâncias Protetoras/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Receptores de Endotelina/metabolismo , Receptores de Lipoxinas/metabolismo , Transdução de Sinais , Suínos , Técnicas de Cultura de TecidosRESUMO
BACKGROUND: Microparticles (MPs) have emerged as a surrogate marker of endothelial dysfunction and cardiovascular risk. This study examined the potential of MPs from senescent endothelial cells (ECs) or from patients with acute coronary syndrome (ACS) to promote premature EC aging and thrombogenicity. METHODS: Primary porcine coronary ECs were isolated from the left circumflex coronary artery. MPs were prepared from ECs and venous blood from patients with ACS (n=30) and from healthy volunteers (n=4) by sequential centrifugation. The level of endothelial senescence was assessed as senescence-associated ß-galactosidase activity using flow cytometry, oxidative stress using the redox-sensitive probe dihydroethidium, tissue factor activity using an enzymatic Tenase assay, the level of target protein expression by Western blot analysis, platelet aggregation using an aggregometer, and shear stress using a cone-and-plate viscometer. RESULTS: Senescence, as assessed by senescence-associated ß-galactosidase activity, was induced by the passaging of porcine coronary artery ECs from passage P1 to P4, and was associated with a progressive shedding of procoagulant MPs. Exposure of P1 ECs to MPs shed from senescent P3 cells or circulating MPs from ACS patients induced increased senescence-associated ß-galactosidase activity, oxidative stress, early phosphorylation of mitogen-activated protein kinases and Akt, and upregulation of p53, p21, and p16. Ex vivo, the prosenescent effect of circulating MPs from ACS patients was evidenced only under conditions of low shear stress. Depletion of endothelial-derived MPs from ACS patients reduced the induction of senescence. Prosenescent MPs promoted EC thrombogenicity through tissue factor upregulation, shedding of procoagulant MPs, endothelial nitric oxide synthase downregulation, and reduced nitric oxide-mediated inhibition of platelet aggregation. These MPs exhibited angiotensin-converting enzyme activity and upregulated AT1 receptors and angiotensin-converting enzyme in P1 ECs. Losartan, an AT1 receptor antagonist, and inhibitors of either mitogen-activated protein kinases or phosphoinositide 3-kinase prevented the MP-induced endothelial senescence. CONCLUSIONS: These findings indicate that endothelial-derived MPs from ACS patients induce premature endothelial senescence under atheroprone low shear stress and thrombogenicity through angiotensin II-induced redox-sensitive activation of mitogen-activated protein kinases and phosphoinositide 3-kinase/Akt. They further suggest that targeting endothelial-derived MP shedding and their bioactivity may be a promising therapeutic strategy to limit the development of an endothelial dysfunction post-ACS.