Endothelial Microparticles Research Articles

Novel Biomarkers of Endothelial Dysfunction in Cardiovascular Diseases

The review analyzes the role of assessing the state of the endothelium in the onset and progression of cardiovascular diseases, stratification of their risks, since endothelial dysfunction (ED) is a crucial predictor of this pathologies. In this regard, this paper presents the modern understanding of the methods for assessing ED, presents the advantages and disadvantages of various techniques. Despite the fact that flow-mediated dilation is widely used as a classical method for studying endothelial function, this technique depends on the physiological state of sensory nerves and calcium-activated potassium channels, cardiac output. This review focuses on new biomarkers for ED such as endothelial microparticles, endoglin and endocan, and discusses the relevance of the criteria for their use in clinical practice. Based on current scientific advances, the authors concluded that among these three newest biomarkers, today, endocan can be considered a more informative and reliable cellular marker of ED. Moreover, the authors have shown that when measured separately, many of the studied classical circulating biomarkers do not provide reliable information about the state of the endothelium, since the endothelial function has a complex physiological nature which therefore raises the question of the advisability of considering a combination of classical and new biomarkers for improving the assessment of the endothelial state.

Positive Association between Endothelium-Platelet Microparticles and Urinary Concentration of Lead and Cadmium in Adolescents and Young Adults.

(1) Background: In previous research, higher levels of urine heavy metals, especially lead and cadmium, have been associated with increased cardiovascular risk. However, there is no information linking exposure to heavy metal to endothelial and platelet microparticles (EMPs and PMPs), particularly in the younger population, which are novel biomarkers of endothelial dysfunction. (2) Methods: From a nationwide database, which was incepted in 1992–2000, screening for renal health among Taiwanese school children, a total of 789 subjects were recruited. Cross-sectional analysis was performed to evaluate the association between serum EMPs/PMPs and urine iron, nickel, copper, cadmium, lead, chromium, manganese, and zinc levels in the adolescent and young adult population. (3) Results: After we adjusted the conventional cardiovascular risk factors, CD31+/CD42a− and CD31+/CD42a+ counts, in subjects’ serum, respective markers of EMP and PMP displayed a significant positive dose-response relationship with urinary lead and cadmium levels. Higher quartiles of urine lead and cadmium levels were associated with an increased risk of higher EMPs/PMPs (≥75th percentile) in a multivariate logistic regression model. (4) Conclusion: Higher urinary lead and cadmium concentrations are strongly associated with endothelium–platelet microparticles in this adolescent and young adult population, which could help explain, in part, the mechanism through which heavy metal exposure results in cardiotoxicity.

Apoptotic microparticles mediate the association between bisphenol A and subclinical atherosclerosis in a young population: A population-based study

Bisphenol A (BPA) exposure is associated with atherosclerotic cardiovascular diseases. The interactions between BPA, extracellular microparticles (MPs), and atherosclerosis are unknown. A total of 103,756 young students participated in the mass urine-screening program in Taiwan between 1992 and 2000 were analyzed. After exclusion, 886 subjects were recruited to test the relationships between serum level of BPA, endothelial and platelet MPs as well as subclinical atherosclerosis represented by carotid artery intima-media thickness (CIMT). We found that an increment of one unit of log-BPA could lead to significant association between thicker CIMT and concentrations of endothelial microparticles and platelet microparticles in the cohort (odds ratio (OR) 1.23, P < 0.001). CD31 + /CD42a- (> 50%, OR 1.229, P = 0.001) and CD31 + /CD42a+ (≦ 50%, OR 1.262, P = 0.017 and > 50%, OR 1.212, P = 0.006) were significantly associated with thicker CIMT in the presence of elevated BPA. When considering the interactions between CD31 + /CD42a- and CD31 + /CD42a+ , we observed increased OR as CD31 + /CD42a- was greater than 50% (CD31 +/CD42a- > 50% and CD31 +/CD42a+ ≦ 50%, OR 1.356, P = 0.029; CD31 +/CD42a- > 50% and CD31 +/CD42a+ > 50%, OR 1.204, P = 0.014). Our study identified a higher risk of thicker CIMT associated with altered MPs in the presence of elevated BPA levels. BPA exposure is associated with endothelial dysfunction and subclinical atherosclerosis in a young population.

Evaluation of endothelial dysfunction and clinical events in patients with early-stage vasculopathy in limited systemic sclerosis.

Limited cutaneous systemic sclerosis (lcSSc) is characterised by vasculopathy contributing to vascular apoptosis, structural and functional changes. The aim of this study was to investigate parameters of endothelial dysfunction and their association to clinical events in lcSSc patients with early-stage vasculopathy. Patients with lcSSc and early-stage vasculopathy defined as absent pre-existing pulmonary arterial hypertension (PAH), digital ulcers, and symptomatic cardiovascular diseases were recruited together with age-, race- and sex-matched controls with primary Raynaud's phenomenon. All subjects underwent measurements of flow-mediated (FMD) and nitroglycerine-mediated dilation (NMD), pulse-wave analysis, and biochemical analysis, including arginine, homoarginine, citrulline, ornithine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and endothelial microparticles (EMP). Clinical events, including EUSTAR index, sicca symptoms, microvascular, skin, renal, gastrointestinal, and pulmonary involvement, were recorded by medical history, physical examination, laboratory parameters, disease-specific questionnaire, electrocardiogram, diagnostic imaging and spirometry. 38 patients with lcSSc and 38 controls were included after screening for eligibility. There was no difference in FMD (p=0.775), NMD (p=0.303), aortic pulse-wave velocity (p=0.662) or in augmentation index (p=0.600) between patients with lcSSc and controls. Higher values of ADMA (p=0.030), SDMA (p=0.025) and borderline significantly higher values for CD31+/CD42b- EMP (p=0.062) were observed in lcSSc patients, also with positive correlations between those parameters. ADMA, SDMA and CD31+/CD42b- were correlated with subclinical PAH, nephropathy and capillary changes. Selected parameters of endothelial dysfunction contribute to clinical events in lcSSc patients with early-stage vasculopathy and endothelial dysfunction seems to be primarily present in microvasculature, while its impact on macrovascular changes in lcSSc is still indistinct.

Elevated circulating endothelial microparticles (EMPs) in prepubertal children born preterm.

Endothelial microparticles (EMPs) act as early biomarkers of endothelial activation and damage. No studies have investigated EMPs in preterm-born individuals. Sixty-three preterm-born children and 52 children born full-term (controls) were studied. Circulating CD62E(+), CD144(+), and CD31(+)/CD42b(-) EMPs were measured in preterm-born children compared to controls; possible associations with cardiovascular risk factors and endothelial function parameters were also assessed. Circulating CD62E(+), CD144(+), and CD31(+)/CD42b(-) EMPs were significantly higher in preterm-born children compared to controls (p = 0.003, p < 0.001, and p < 0.001, respectively). Preterm birth was recognized as an independent predictor of each EMP subpopulation studied; moreover, the mean pressure and velocity of pulmonary artery were independently correlated with CD62E(+) (β = 0.20, p = 0.04) and CD144(+) EMPs (β = 0.22, p = 0.02), respectively, whereas age (β = 0.21, p = 0.03) and being born SGA (β = 0.26, p = 0.01) correlated independently with CD31(+)/CD42b(-) EMPs in the study population. Furthermore, diastolic blood pressure (β = 0.24, p = 0.04), being born SGA (β = 0.24, p = 0.04) and the hyperemic peak velocity of the brachial artery (β = -0.65, p = 0.02) were independently associated with CD31(+)/CD42b(-) EMPs in the preterm-born group. Circulating EMPs were higher in preterm-born children compared to children born full-term. Whether EMPs could act, in clinical practice, as a complementary tool for non-invasive evaluation of endothelium in preterm-born children, remains under investigation. Circulating endothelial microparticles (EMPs) are small membrane vesicles released from endothelial cells and they act as novel biomarkers of endothelial activation and damage. No studies have investigated circulating EMPs in preterm-born individuals. Circulating EMPs were significantly higher in prepubertal preterm-born children compared to children born at term. In the preterm-born group, the hyperemic peak velocity of the brachial artery was independently associated with CD31(+)/CD42b(-) EMPs. Whether assessment of circulating EMPs could act, in clinical practice, as a complementary tool for non-invasive evaluation of endothelium in preterm-born children, remains to be defined in future investigations.

Endothelial microparticle-associated protein disulfide isomerase increases platelet activation in diabetic coronary heart disease.

Background: Endothelial microparticles (EMPs) carrying the protein disulfide isomerase (PDI) might play a key role in promoting platelet activation in diabetes. This study aimed to examine the activation of platelets, the amounts of MPs, PMPs, and EMPs, and the concentration and activity of PDI in patients with diabetic coronary heart disease (CHD) and non-diabetic CHD.Methods: Patients with CHD (n=223) were divided as non-diabetic CHD (n=121) and diabetic CHD (n=102). Platelet activation biomarkers, circulating microparticles (MPs), the concentration of protein disulfide isomerase (PDI), and MP-PDI activity were determined. The effect of EMPs on platelet activation was investigated in vitro. Allosteric GIIb/IIIa receptors that bind to PDI were detected by a proximity ligation assay (PLA).Results: Platelet activation, platelet-leukocyte aggregates, circulating MPs, EMPs, PDI, and MP-PDI activity in the diabetic CHD group were significantly higher than in the non-diabetic CHD group (P<0.05). Diabetes (P=0.006) and heart rate <60 bpm (P=0.047) were associated with elevated EMPs. EMPs from diabetes increased CD62p on the surface of the platelets compared with the controls (P<0.01), which could be inhibited by the PDI inhibitor RL90 (P<0.05). PLA detected the allosteric GIIb/IIIa receptors caused by EMP-PDI, which was also inhibited by RL90.Conclusions: In diabetic patients with CHD, platelet activation was significantly high. Diabetes and heart rate <60 bpm were associated with elevated EMPs and simultaneously increased PDI activity on EMP, activating platelets through the allosteric GPIIb/IIIa receptors.

Association between plasma endothelial microparticles and contrast-induced nephropathy in patients underwent coronary angiography.

We aim to investigate the association between plasma endothelial microparticles (EMPs) and contrast-induced nephropathy of patients underwent coronary angiography.The patients were divided into normal renal function group and renal dysfunction group based on the estimated glomerular filtration rate (eGFR). Among the 180 cases, 117 received determination of EMP and serum creatinine after percutaneous coronary intervention (PCI) and/or coronary angiography. The patients were divided into contrast-induced-nephropathy (CIN) group and non-CIN group. EMPs collection and determination were performed, together with biochemical analysis and digital subtraction angiography (DSA) analysis.Spearman correlation showed that the expression of EMP was negatively correlated with eGFR (r = –0.201, P < .01). The serum hypersensitive C-reactive protein (hs-CRP), cystatin C (Cys-C), uric acid (UA) were significantly higher in CIN group than that in the non CIN group. Spearman correlation showed that the expression of EMP was positively correlated with serum interleukin-6 (IL-6, r = 0.393, P < .01). The expression of EMP was positively correlated with serum hs-CRP (r = 0.360, P < .01). Logistic regression analysis showed that the levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), eGFR, UA, and Cys-C were correlated with the incidence of contrast induced nephropathy.In patients with contrast-induced-nephropathy, the plasma EMPs were significantly increased after coronary angiography. The expression of plasma EMPs may play a role in the occurrence of contrast-induced-nephropathy.

Effects of acute moderate-intensity exercise at different duration on blood pressure and endothelial function in young male patients with stage 1 hypertension

ABSTRACT Purpose The studies regarding the effects of exercise duration on blood pressure have reported inconsistent and conflicting results. Nitric oxide (NO) is a well-known vasodilator released by endothelial cells, and endothelial microparticles (EMPs) are membranous vesicles released into the circulation from activated or apoptotic endothelial cells, both of whose level can reflect the endothelial function. But few studies have been done to explore the effect of exercise duration on blood pressure and endothelial function, especially, the EMPs response to exercise in young male patients with hypertension. This study aimed to investigate the blood pressure response during moderate-intensity exercise performed in different durations and the acute effects on post-exercise hypotension and endothelial function in hypertensive patients. Methods Eighteen young male hypertensive patients who did not take antihypertensive drugs were recruited in this study. They randomly performed twice exercises on a cycle ergometer at a moderate intensity of 40%–50% of their HR reserve; one was 20 min (E20 session), the other one was 40 min (E40 session); there was 1-week break between the two exercises. Blood pressure was monitored by the YUWELL blood pressure monitor at rest, every 5 min during exercise, and 3 and 6 min post-exercise. The level of NO (nitrate/nitrite reduction) and EMPs (flow cytometry) in plasma were detected before and immediately following exercise. CD31+/CD42b− events were classified as EMPs and events per microliter plasma were calculated. This study was approved by the Beijing Sport University Institutional Review Board (protocol number 2019087 H). Results Mean age of patients was 34.8 ± 3.5 yrs, and BMI was 27.6 ± 2.7 kg/m2. Systolic blood pressure (SBP) in the two sessions increased significantly during exercise. The SBP in the E20 session increased by 37 mmHg (P < .01) at 5 min during exercise and remained stable afterward. In the E40 session, the SBP increased by 35 mmHg (P < .01) at 5 min during exercise and was stable at 5 through 25 min, decreased by 8 mmHg at 25 through 35 min during exercise, and then stabilized (P < .01). There was no obvious change of diastolic blood pressure (DBP) in the two sessions during exercise. In the E20 session, SBP at 6 min following exercise was no different from the rest; in the E40 session, SBP at 6 min following exercise was 14 mmHg lower than at the rest (P < .01). DBP in the E20 session was the same as rest at 3 min following exercise and decreased by 4 mmHg at 6 min following exercise compared with the rest (P < .05), while DBP in the E40 session decreased by 3 mmHg at 3 min following exercise compared with the rest (P < .05). The plasma NO levels of E20 and E40 increased significantly following exercise (P < .01 for both). There was no difference in plasma NO level between the two sessions pre- and post-exercise, but the increased magnitude of NO level in E40 was greater than that in E20 (24.47% vs. 9.24%, P < .01). The plasma EMPs level of E20 and E40 decreased significantly following exercise (P < .01 for both). There was no difference in plasma EMPs level between the two sessions pre- and post-exercise, but the decreased magnitude of EMPs level in E40 was greater than that in E20 (15.66% vs. 8.00%, P < .01). Conclusion There is no exaggerated blood pressure response to 20-min and 40-min acute moderate-intensity exercise in young hypertensive men with no antihypertensive drugs. Both 20-min and 40-min acute moderate exercise can reduce the rest blood pressure, and improve endothelial function by increasing NO and decreasing EMPs in young male patients with hypertension, and the effects of 40-min exercise on lowering SBP and improving endothelial function are better than that of 20-min.

Modeling NO Biotransport in Brain Using a Space-Fractional Reaction-Diffusion Equation.

Nitric oxide (NO) is a small gaseous molecule that is involved in some critical biochemical processes in the body such as the regulation of cerebral blood flow and pressure. Infection and inflammatory processes such as those caused by COVID-19 produce a disequilibrium in the NO bioavailability and/or a delay in the interactions of NO with other molecules contributing to the onset and evolution of cardiocerebrovascular diseases. A link between the SARS-CoV-2 virus and NO is introduced. Recent experimental observations of intracellular transport of metabolites in the brain and the NO trapping inside endothelial microparticles (EMPs) suggest the possibility of anomalous diffusion of NO, which may be enhanced by disease processes. A novel space-fractional reaction-diffusion equation to model NO biotransport in the brain is further proposed. The model incorporates the production of NO by synthesis in neurons and by mechanotransduction in the endothelial cells, and the loss of NO due to its reaction with superoxide and interaction with hemoglobin. The anomalous diffusion is modeled using a generalized Fick’s law that involves spatial fractional order derivatives. The predictive ability of the proposed model is investigated through numerical simulations. The implications of the methodology for COVID-19 outlined in the section “Discussion” are purely exploratory.

Effects of structured home-based exercise training on circulating endothelial progenitor cells and endothelial function in patients with intermittent claudication.

Exercise training improves walking capacity in patients with intermittent claudication (IC). Endothelial progenitor cells (EPCs), endothelial microparticles (EMPs), and endothelial dysfunction could play a role in this process. We measured EPCs and EMPs in a group of 60 patients with IC, and in a control group of 20 individuals without IC, before a treadmill test and 2, 24, and 48 hours after the test. Thirty patients with IC were randomly assigned to perform a 12-week home-based exercise training program. The EPC count, flow-mediated dilation (FMD) of the brachial artery, pain-free walking time (PFWT), and maximum walking time (MWT) were measured at the baseline and after the exercise training program. In patients with IC, EMPs significantly increased 2 hours after the treadmill test, whereas EPCs significantly increased after 24 hours. Among the subjects assigned to complete the training program, we observed a significant increase in the number of EPCs after 12 weeks, as well as an improvement in FMD, PFWT, and MWT. A significant correlation between the variation of EPCs, FMD, and MWT was found. The increase of EPCs and FMD were independent determinants of the walking capacity improvement, without significant interaction. Our results suggest that EPCs mobilization contributes to the improvement of walking capacity in patients with IC undergoing structured physical training. A number of different, partly independent, mechanisms are involved in this process, and our results highlight the potential role of EMPs release and endothelial function improvement. ClinicalTrials.gov Identifier: NCT04302571.

The Vasculopathy of Juvenile Dermatomyositis: Endothelial Injury, Hypercoagulability, and Increased Arterial Stiffness.

Vasculopathy is considered central to the pathogenesis of juvenile dermatomyositis (DM) and is associated with severe extramuscular manifestations. We undertook this study to investigate the hypothesis that the vasculopathy of juvenile DM can be noninvasively tracked by examining biomarkers of endothelial injury, subclinical inflammation, hypercoagulability, and vascular arterial stiffness. The study population was a UK cohort of children with juvenile DM. Circulating endothelial cells (CECs) and microparticles (MPs) were identified using immunomagnetic bead extraction and flow cytometry, respectively. Plasma thrombin generation was determined using a fluorogenic assay. Cytokine and chemokine levels were measured by electrochemiluminescence. Arterial stiffness was assessed using pulse wave velocity (PWV). Results were expressed as the median and interquartile range (IQR), and statistical significance was assessed using nonparametric analyses. Ninety patients with juvenile DM and 79 healthy control subjects were included. The median age of the patients was 10.21 years (IQR 6.68-13.40), and the median disease duration was 1.63 years (IQR 0.28-4.66). CEC counts were higher in all patients with juvenile DM compared to controls (median 96 cells/ml [IQR (40-192] and 12 cells/ml [IQR 8-24], respectively; P < 0.0001). Circulating MP numbers were also significantly higher in patients with active juvenile DM compared to controls (median 204.7 × 103 /ml [IQR 87.9-412.6] and 44.3 × 103 /ml [IQR 15.0-249.1], respectively; P < 0.0001). MPs were predominantly of platelet and endothelial origin. Enhanced plasma thrombin generation was demonstrated in patients with active juvenile DM compared to those with inactive disease (P = 0.0003) and controls (P < 0.0001). Carotid-radial PWV adjusted for age was increased in patients with juvenile DM compared to controls (P = 0.003). We observed increased endothelial injury and increased levels of proinflammatory cytokines in patients with active juvenile DM. MP profiles reflected distinct disease activity status in juvenile DM and are markers of vascular pathology, platelet activation, and thrombotic propensity. Ongoing long-term vascular injury may result in increased arterial stiffness in patients with juvenile DM.

Abstract P031: Endothelial Microparticles In Pediatric Obesity

Introduction: Endothelial activation represents one of the earliest signs of the atherosclerotic process. Microparticles (MPs) in plasma, particularly endothelial MPs (EMPs) are reproducible biomarkers of endothelial dysfunction with a simple blood draw. The goal of this study was to examine the association of obesity with MPs, EMPs (CD31+/CD41– and/or CD 144+/CD31–), and activated EMPs (CD106+). Hypothesis: We hypothesized that higher body mass index (BMI), body fat percent (BF%), and visceral adipose tissue (VAT) would be associated with higher levels of MPs, EMPs, and activated EMPs. Methods: This was a cross-sectional study of 280 children and adolescents ages 8-18 years old. Whole venous blood was collected and processed for platelet free-plasma (PFP) collection less than 3 hours after being drawn. PFP samples were prepared using serial centrifugations and then frozen as 100 μl aliquots at -80 ° C. MPs were measured using flow cytometry with size ranging from 0.3 to 1.0 μm. EMPs were defined as MP with CD31+/CD41– and/or CD 144+/CD31–. Active EMP was identified as EMP with CD 106+. BF% and VAT were measured using dual X-ray absorptiometry. Linear (total MPs and EMPs) and logistic (activated EMPs) regression models were used to examine the associations with adiposity group, BF%, and VAT, adjusting for Tanner stage, sex, and race. Results: The mean age of the cohort was 12.7 years, consisting of 147 females and BMI distribution: 112 normal-weight, 77 overweight/obesity, 91 severe obesity. Youth with overweight/obesity and severe obesity had higher numbers of total MPs (28,690 per μL PFP/g [-2,315, 59,695], p=0.07 and 52,744 per μL PFP/g [22,163, 83,324], p&lt;0.001, respectively) and total EMPs (350 per μL PFP/g [81, 618], p=0.011 and 278 per μL PFP/g [13, 543], p=0.040, respectively) compared to peers with normal weight. In the entire cohort, higher BF% was associated with higher MPs (1,646 per μL PFP per percent [509, 2,783], p=0.005) and EMPs (11 per μL PFP per percent [2, 21], p=0.023), and higher VAT was associated with higher MPs (34 per μL PFP/g [11, 57], p=0.004) but not EMPs. Logistic regression analysis showed higher odds of active EMPs (odds ratio, 1.72 [1.0, 2.97], p=0.0502) in those with a BMI &gt;85 th percentile compared to youth with a BMI &lt;85 th percentile. In the entire cohort, BF% (odds ratio, 1.02 [1.00, 1.04], p=0.108) and VAT (odds ratio, 1.00 [1.00, 1.00], p=0.472) were not significantly associated with active EMPs. Conclusions: Higher levels of endothelial cell damage and activation were associated with obesity and excess adiposity in youth. The potential role of MPs and EMPs as useful biomarkers of cardiovascular disease risk merits further study.

IL-33 / ST2 Signaling Promotes TF Expression by Regulating NF-κB Activation in Coronary Artery Endothelial Microparticles

IntroductionInterleukin (IL)-33 was previously shown to induce angiogenesis and inflammatory activation of endothelial Microparticles(EMPs). Tissue factor (TF) plays a central role in hemostasis and thrombosis.Material and methodsThe study analyzed the coronary blood of level of CD31+EMPs, TF protein and IL-33 protein in Acute Myocardial Infarction (AMI) and stable coronary artery disease (SCAD) patients. Human coronary artery endothelial cells (HCAECs) were treated with IL-33 to obtain EMPs. The TF activity of EMPs was tested by Thermo Fisher by adding the TF antibody. Furthermore, TF and Tissue Factor Pathway Inhibitor (TFPI) protein were tested by ELISA. Finally, NF-κB inhibitor dimethyl fumarate (DMF) and soluble extracellular domain of ST2 coupled to the Fc fragment of human IgG1 (sST2) were added to HCAECs which were treated with IL-33, and the TF protein level was also tested by ELISA.ResultsThe AMI patients had higher level of CD31+EMPs, TF protein and IL-33 protein than the SCAD patients in coronary artery. In AMI patients (N=27), the IL-33 protein positively correlated with CD31+EMPs (r=0.794, p&lt;0.01). According to the ROC curve analysis, the AUC of CD31+EMPs, TF protein and IL-33 protein were 0.888, 0.962 and 0.778 respectively. In the cell culture, the TF activity and TF protein in EMPs increased gradually with time of intervention by the treatment of IL-33. IL-33 binding to the ST2 receptor promoted TF expression by regulating NF-κB activation in EMPs of HCAECs.ConclusionsActivated endothelial cells and EMPs they released simultaneously express TF, which is a risk factor for cardiovascular disease.

Vascular inflammation in moderate‐to‐severe atopic dermatitis is associated with enhanced Th2 response

In atopic dermatitis (AD), some studies have shown an association with increased cardiovascular disease in certain populations. However, other investigations found modest or no association. Despite conflicting results, molecular profiling studies in both AD skin and blood have demonstrated upregulation of atherosclerosis and cardiovascular risk-related markers. However, the underlying mechanisms connecting AD to vascular inflammation/atherosclerosis are unknown. In this study, we aim to determine factors associated with vascular inflammation/atherosclerosis in AD patients. We used 18-FDG PET-CT to characterize vascular inflammation in AD patients and healthy subjects. In parallel, we assessed their skin and blood immune profiles to determine AD-related immune biomarkers associated with vascular inflammation. We also assessed levels of circulating microparticles, which are known to be associated with increased cardiovascular risk. We found significant correlations between vascular inflammation and Th2-related products in skin and blood of AD patients as well as atherosclerosis-related markers that were modulated by dupilumab. Circulating levels of endothelial microparticles were significantly higher in severe AD patients and tended to correlate with vascular inflammation assessed by PET-CT. Vascular inflammation in AD is associated with enhanced Th2 response and clinical severity, which may explain cardiovascular comorbidities observed in select AD populations. Larger prospective studies are needed to further evaluate vascular inflammation and cardiovascular events and mortality in AD patients. Finally, as dupilumab treatment demonstrated significant modulation of atherosclerosis-related genes in AD patients compared to placebo, these data suggest that modulation of vascular inflammation with systemic treatment should be explored in patients with AD.

Gly14]-Humanin Ameliorates High Glucose-Induced Apoptosis by Inhibiting the Expression of MicroRNA-155 in Endothelial Microparticles.

BackgroundHumanin, a newly emerging endogenously expressed cytoprotective peptide, has been shown to have anti-apoptotic properties effects by protecting neuronal cells injury. Endothelial microparticles (EMPs) are considered as vital mediators in intercellular communication. EMPs may regulate various physiological and pathological processes by transferring mRNAs and microRNAs (miRNAs) to recipient cells.MethodsEMPs were isolated from human umbilical vein endothelial cells (HUVECs) by ultracentrifugation. EMPs were characterized by transmission electron microscopy and nanoparticle tracking analyses. Observation of EMPs uptake into HUVECs and the number of EMPs were realized by confocal microscopy. The expression of miR-155 was examined using real-time PCR. Cell apoptosis was examined by flow cytometry assay.ResultsWe found that high glucose (HG) increased the number of EMPs and upregulated the expression of miR-155 contained within EMPs, which was mitigated by HNG pretreatment. miR-155 overexpression in EMPs reversed the effects of HNG pretreatment and increased apoptosis of target cells. Effects of HNG pretreatment on HG-treated endothelial cells (ECs) were mitigated after miR-155 mimic transfection into HUVECs while were augmented after miR-155 inhibitor transfection into HUVECs.ConclusionHNG inhibited HG-induced apoptosis of ECs and the effect of HNG may be mediated by inhibiting the transfer of EMPs miR-155 from HG-induced HUVECs to normal cells. This study provides a new direction for biological products related to humanin to treat vascular complications associated with all forms of diabetes mellitus.

Circulating endothelial microparticles: a promising biomarker of acute kidney injury after cardiac surgery with cardiopulmonary bypass

BackgroundCurrent diagnostic strategies for acute kidney injury (AKI) after cardiac surgery with cardiopulmonary bypass (CPB) are nonspecific and limited. Previously, we demonstrated that circulating microparticles (MPs) in patients with valve heart disease (VHD) and congenital heart diseases (CHD) induce endothelial dysfunction and neutrophil chemotaxis, which may result in kidney injury. We also found that circulating MPs increase after cardiac surgery with CPB and are related to cardiac function. However, the relationship between circulating MPs and AKI after CPB is unknown.MethodsEighty-five patients undergoing cardiac surgery with CPB were enrolled. Patients were divided into AKI and non-AKI groups based on the serum creatinine levels at 12 h and 3 d post-CPB. Circulating MPs were isolated from plasma, and their levels including its subtypes were detected by flow cytometer. Independent risk factors for the CPB-associated AKI (CPB-AKI) were determined by multivariate logistic regression analysis. Receiver operating characteristic (ROC) analysis was used to measure the prognostic potential of CPB-AKI.ResultsThe morbidity of AKI at 12 h and 3 d after cardiac surgery with CPB was 40% and 31.76%, respectively. The concentrations of total MPs and platelet-derived MPs (PMP) remained unchanged at 12 h and then increased at 3 d post-CPB, while that of endothelial-derived MPs (EMP) increased at both time points. In patients with AKI, PMP and EMP were elevated compared with the patients without AKI. However, no significant change was detected on monocyte-derived MPs (MMP) at 12 h and 3 d post-CPB. The logistic regression analysis showed that EMP was the independent risk factor for AKI both at 12 h and 3 d post-CPB. The area under ROC for the concentrations of EMP at 12 h and 3 d post-CPB was 0.86 and 0.91, with the specificity up to 0.88 and 0.91, respectively.ConclusionsCirculating EMP may serve as a potential biomarker of AKI after cardiac surgery with CPB.

Microparticles: An Alternative Explanation to the Behavior of Vascular Antiphospholipid Syndrome.

Antiphospholipid syndrome is an autoimmune disease characterized by the persistent presence of antiphospholipid antibodies, along with occurrence of vascular thrombosis and pregnancy morbidity. The variety of antiphospholipid antibodies and their related mechanisms, as well as the behavior of disease in wide groups of patients, have led some authors to propose a differentiation of this syndrome into two independent entities: vascular and obstetric antiphospholipid syndrome. Thus, previous studies have discussed whether specific autoantibodies may be responsible for this differentiation or, in contrast, how the same antibodies are able to generate two different clinical presentations. This discussion is yet to be settled. The capability of serum IgG from patients with vascular thrombosis to trigger the biogenesis of endothelial cell-derived microparticles in vitro is one of the previously discussed differences between the clinical entities of antiphospholipid syndrome. These vesicles constitute a prothrombotic mechanism as they can directly lead to clot activation in murine models and recalcified human plasma. Nevertheless, other indirect mechanisms by which microparticles can spread a procoagulant phenotype could be critical to understanding their role in antiphospholipid syndrome. For this reason, questions regarding the cargo of microparticles, and the signaling pathways involved in their biogenesis, are of interest in attempting to explain the behavior of this autoimmune disease.

Патогенетичне значення інсулінорезистентності та ендотеліальної дисфункції у розвитку ускладнень вагітності у жінок з ожирінням та прееклампсією

The purpose of the study was to analyze the effect of insulin resistance and endothelial dysfunction on the development of pregnancy complications in a group of obese women and women with pre-eclampsia. Materials and methods. To achieve this goal, we examined 393 pregnant women on the basis of the Poltava city clinical maternity hospital at the early (9-13 weeks) and later gestation (34-38 weeks). Pregnant women according to a degree of obesity and presence of pre-eclampsia were devided into three groups: the first group – 149 pregnant women with obesity of the first degree, the second group – 73 pregnant women with obesity of the second degree, the third group – 46 pregnant women with obesity of the third degree, the fourth group – 6 pregnant women with physiological body weight and pre-eclampsia, the fifth group – 6 pregnant women with obesity of the first degree and pre-eclampsia, the sixth group – 6 pregnant women with obesity of 2nd-3rd degrees and pre-eclampsia. The index of insulin resistance HOMA-IR, the level of expression of CD32+CD40+ of circulating endothelial microparticles, which was determined by flow cytophluorimetry, were determined in pregnant women. In women of experimental and control groups the frequency of complications of pregnancy was compared. Results and discussion. In pregnant women with obesity as a result of increased insulin resistance and reducing glucose absorption by tissues there are preconditions for the development of energy insufficiency, as well as an increase in the amount of CD32+CD40+ of circulating endothelial microparticles in the peripheral blood in pregnant women, who had pre-eclampsia, which joined. It confirms the existence of endothelial dysfunction. The deterioration of these indicators progressed as the severity of obesity increases. Comparisons of the frequency of pregnancy complications in experimental and control groups of women indicate that obesity is a risk factor for the emergence of these complications of pregnancy. Conclusion. Thus, the progression of insulin resistance during pregnancy in a group of women with obesity of varying degrees and induced endothelial dysfunction is a pathogenic basis for energy insufficiency and reduction of adaptive mechanisms of pregnant women with obesity, as convincingly indicates an increase in the frequency of obstetric and perinatal complications

Prevention of preeclampsia in pregnant women with obesity

Reducing the occurrence of preeclampsia is one of the key tasks in modern obstetrics, especially in pregnant women with concomitant obesity, who are at high risk for preeclampsia, the leading pathogenetic segment of which is endothelial dysfunction. The purpose of this work is to evaluate the effectiveness of the integrated therapeutic and preventive complex (TPC) in order to prevent preeclampsia in pregnant women. These parameters were evaluated using such markers as the concentration of vascular endothelial growth factor (VEGF) in blood serum and the content of circulating endothelial microparticles (CEM) CD32+CD40+ in peripheral blood in pregnant women with obesity of varying severity over the course of treatment we proposed. 110 pregnant women were included in the study: women with physiological body weight (n=26); women with class I obesity (n=42), and women with class II-III obesity. The groups of pregnant women with concomitant obesity were divided into two equal subgroups; one of the subgroups received the TPC (acetylsalicylic acid, calcium supplements, L-arginine, diosmin). The findings obtained demonstrate a significant improvement of endothelial status over the course of the therapy that is manifested with an increase in the serum VEGF concentration and a decrease in the content of CD32+CD40+ CEM in the peripheral blood. Our clinical assessment of pregnancy course, childbirth and the postpartum period in women with obesity and physiological body weight has shown a decrease in the occurrence of complications due to taking the integrated TPC. We have registered a decrease in the incidence of preeclampsia, placental dysfunction, occurrence of miscarriage, operative delivery and postpartum complications.

Disturbed Blood Flow Acutely Increases Endothelial Microparticles and Decreases Flow Mediated Dilation in Patients With Heart Failure With Reduced Ejection Fraction.

IntroductionDisturbed blood flow, characterized by high retrograde and oscillatory shear rate (SR), is associated with a proatherogenic phenotype. The impact of disturbed blood flow in patients with heart failure with reduced ejection fraction (HFrEF) remains unknown. We tested the hypothesis that acute elevation to retrograde and oscillatory SR provoked by local circulatory occlusion would increase endothelial microparticles (EMPs) and decrease brachial artery flow-mediated dilation (FMD) in patients with HFrEF.MethodsEighteen patients with HFrEF aged 55 ± 2 years, with left ventricular ejection fraction (LVEF) 26 ± 1%, and 14 control subjects aged 49 ± 2 years with LVEF 65 ± 1 randomly underwent experimental and control sessions. Brachial artery FMD (Doppler) was evaluated before and after 30 min of disturbed forearm blood flow provoked by pneumatic cuff (Hokanson) inflation to 75 mm Hg. Venous blood samples were collected at rest, after 15 and 30 min of disturbed blood flow to assess circulating EMP levels (CD42b−/CD31+; flow cytometry).ResultsAt rest, FMD was lower in patients with HFrEF compared with control subjects (P < 0.001), but blood flow patterns and EMPs had no differences (P > 0.05). The cuff inflation provoked a greater retrograde SR both groups (P < 0.0001). EMPs responses to disturbed blood flow significantly increased in patients with HFrEF (P = 0.03). No changes in EMPs were found in control subjects (P > 0.05). Disturbed blood flow decreased FMD both groups. No changes occurred in control condition.ConclusionCollectively, our findings suggest that disturbed blood flow acutely decreases FMD and increases EMP levels in patients with HFrEF, which may indicate that this set of patients are vulnerable to blood flow disturbances.