Apoptosis In Systemic Lupus Erythematosus Research Articles

LncRNA SNHG1 serves as a biomarker for systemic lupus erythematosus and participates in the disease progression.

LncRNAs play an important role in autoimmune diseases. The purpose of this study was to explore the role of lncRNA SNHG1 in systemic lupus erythematosus (SLE), and laid a theoretical foundation for the study of SLE. The basic clinical information of all subjects was first collected for statistical analysis, and SNHG1 expression in the serum of all subjects was detected by RT-qPCR. The value of SNHG1 in the diagnosis of SLE was assessed by ROC. The correlation between SNHG1 and each blood sample index was analyzed by Pearson correlation analysis. The role of SNHG1 in primary peripheral blood mononuclear cells (PBMCs) apoptosis was explored. SNHG1 expression is relatively upregulated in patients with SLE compared to healthy people. SNHG1 expression was positively correlated with SLEDAI score, IgG, CRP, and ESR, and negatively correlated with C3 and C4. ROC indicated that SNHG1 has the potential to assistin the diagnosis of SLE. PBMCs apoptosis in SLE was higher than that in control group, the knockdown and overexpression of SNHG1 could correspondingly inhibit and promote PBMCs apoptosis. SNHG1 has the potential to be a diagnosis marker for SLE and may be involved in regulating PBMCs apoptosis.

CNT-FET for sensitive hydrogen peroxide biosensing via immobilized Cytochrome c

H2O2 is an effective substance in the body which contributes to gene expression, insulin metabolism and determining cell shapes. However, a high concentration of H2O2 is harmful to the body and can cause various diseases such as colitis wounds, sepsis disease, lymphocyte proliferation and macrophage apoptosis in systemic lupus erythematosus. In this study, a Cyt c/cMWCNTs/FET was designed to real-time detect H2O2 via immobilized Cyt c on the cMWCNTs/FET surface. The performance of the Cyt c/cMWCNTs/FET biosensor was studied under various parameters such as cMWCNTs and Cyt c concentrations, as well as different pH values. When H2O2 was added to the reaction chamber of the Cyt c/cMWCNTs/FET, the output current of the Bio-FET was reduced, which was attributed to H2O2 detection. The linear response range of this Cyt c/cMWCNT/FET was 10.0 fM to 1.0 nM. The limit of detection and response time of this platform were determined to be 9.13 fM and around 1.0 s, respectively. Also, the operation of the Cyt c/cMWCNTs/FET in the presence of glucose, leucine, tyrosine and ascorbic acid as interfering substances was selective towards H2O2.

Effects of Atorvastatin on T-Cell Activation and Apoptosis in Systemic Lupus Erythematosus and Novel Simulated Interactions With C-Reactive Protein and Interleukin 6.

ObjectiveWe study activation of T helper 17 (Th17) and regulatory T (Treg) cells and induction of apoptosis in cells from patients with systemic lupus erythematosus (SLE) compared with controls and effects of atorvastatin and its simulated interactions with other compounds.MethodsMononuclear cells from 10 patients with SLE and 10 controls were cultured in conditions that induce Th17 and/or Treg cell polarization and/or apoptosis and were studied by FACScan. Gene expression was determined by quantitative real‐time reverse transcription–polymerase chain reaction. Cytokines in plasma were determined by enzyme‐linked immunosorbent assay. The Search Tool for Interactions of Chemicals (STITCH) was used to retrieve information regarding the binding properties of atorvastatin.ResultsAmong patients with SLE, the proportion of Th17 (CD4+IL17+) cells was higher compared with controls after activation, with Th17 or Treg polarizing cytokines, phorbol myristate acetate, and ionomycin. In contrast, Treg cells (CD4+CD25+CD127dim/−) frequencies were lower. CD95 stimulation induced relatively more apoptosis in Treg cells and less in Th17 cells, as compared with controls. Addition of atorvastatin normalized Th17/Treg cell balance and apoptosis induction. Accordingly, the ratio of RORC/FoxP3 decreased in patients with SLE. Interleukin 17 and interleukin 6 (IL‐6) levels were increased in patients with SLE. Atorvastatin interacted strongly with C‐reactive protein (CRP) and also significantly with IL‐6.ConclusionThere is a higher proportion of Th17 cells and a lower proportion of Treg cells in patients with SLE after activation. Th17 cells were more resistant than Treg cells to CD95‐induced apoptosis in SLE. Atorvastatin normalized these effects. Our findings reveal a novel mechanism behind the imbalance of Th17/Treg cells with implications for treatment in SLE. We determine for the first time simulated interaction between atorvastatin, CRP, and IL‐6, implying a novel role of atorvastatin.

Role of MiR-98 and Its Underlying Mechanisms in Systemic Lupus Erythematosus.

T-lymphocyte apoptosis plays a critical role in the pathogenesis of systemic lupus erythematosus (SLE). However, the underlying regulatory mechanisms of apoptosis in SLE remain unclear. The aim of this study was to explore the role of miR-98 in SLE and its underlying mechanisms. Western blotting and quantitative reverse transcription PCR (qRT-PCR) were used to analyze miR-98 and Fas expression. Luciferase reporter assays were performed to identify miR-98 targets. To modify miRNA levels, miR-98 mimics and inhibitor were transfected into cells. A lentiviral construct was used to overexpress the level of Fas in SLE CD4+ T cells. Gene and protein expression were determined by qRT-PCR and Western blotting. Apoptosis levels were evaluated by annexin V staining and flow cytometry. Compared to those of healthy donors, miR-98 was downregulated in SLE CD4+ T cells, whereas Fas mRNA and protein expression were upregulated. Upregulation of miR-98 by mimic transfection protected Jurkat cells against Fas-mediated apoptosis at both mRNA and protein levels, while miR-98 inhibitor induced the completely opposite effect. Luciferase reporter assays demonstrated that miR-98 directly targeted Fas mRNA. Further, miR-98 inhibitor induced apoptosis in primary healthy CD4+ T cells through the Fas-caspase axis, while upregulation of miR-98 in SLE CD4+ T cells led to the opposite effect. The current study revealed that downregulation of miR-98 induces apoptosis by modulating the Fas-mediated apoptotic signaling pathway in SLE CD4+ T cells. These results suggest that miR-98 might serve as a potential target for SLE treatment.

124 MicroRNA-3926 promotes apoptosis of SLE CD4+ T cells through inhibiting autophagy by targeting ATG5

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by impaired T lymphocyte homeostasis, resulting in increased apoptosis and T cell hyperactivation. A wealth of studies has implicated autophagy in the pathogenesis of SLE. However, the mechanisms underlying the regulation of autophagy and apoptosis in SLE remain unclear. The aim of this study was to explore the role of miR-3926 in crosstalk of autophagy and apoptosis in SLE. By qRT-PCR and western blot, we found that the expression of miR-3926 was significantly up-regulated in SLE CD4+ T cells compared with in healthy donors and was inversely correlated with the expression of ATG5, whereas ATG5 mRNA and protein expression was down-regulated. Luciferase reporter assays demonstrated that miR-3926 directly targeted ATG5 mRNA. Up-regulation of miR-3926 by mimic transfection inhibited autophagy activity in healthy donor CD4+ T cells by down-regulating ATG5 expression, and the modulated autophagy was closely associated with both caspase-mediated apoptosis and T cell overactivation observed in SLE, whereas miR-3926 inhibitors led to the complete opposite effects in SLE CD4+ T cells. Collectively, our data suggest that miR-3926 promotes apoptosis in SLE CD4+ T cells through inhibiting autophagy and contributes to T cell autoreactivity in SLE by directly targeting ATG5. Our findings provide new insight into the molecular mechanisms underlying CD4+ T cell autophagy and apoptosis crosstalk, and suggest a possible efficacious adjuvant therapy for SLE patients.

Lymphopenia relating to T-lymphocyte apoptosis in systemic lupus erythematosus

Lymphopenia relating to T-lymphocyte apoptosis in systemic lupus erythematosus

The pathway of estradiol-induced apoptosis in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a disease with unknown etiology. The pathologic role of sex hormones and apoptosis in SLE has often been discussed. We studied the effects of estradiol in the pathway of induced apoptosis in Iranian SLE patients. T lymphocytes from 35 SLE patients and 20 age-matched controls were isolated and cultured in the presence of 10(-8)M 17-β estradiol. The expression levels of Fas, Fas ligand (FasL), Bcl-2, caspase-8, and caspase-9 mRNAs were determined semiquantitatively in comparison to the expression level of beta actin RNA. Estradiol exposure did not have any significant effects on the expression levels of Fas, Bcl-2, and caspase-9 in SLE patients and controls. However, the expression levels of FasL and caspase-8 were significantly increased in SLE patients, but not in controls. This suggests the probable involvement of extrinsic apoptosis pathway in estradiol-induced apoptosis in SLE.

Lupus Nephritis: Role of Antinucleosome Autoantibodies

The discovery of autoantigen clustering in blebs at the surface of apoptotic cells boosted research on the role of apoptosis in systemic lupus erythematosus (SLE) and led to the discovery of autoantigen modification during apoptosis. Normally, apoptotic cells are cleared efficiently and swiftly. However, it became clear that in SLE insufficient removal of apoptotic material leads to the release of these modified autoantigens. This creates the danger that these modified autoantigens are recognized by the immune system. Indeed, dendritic cells, the professional antigen-presenting cells, phagocytose these modified autoantigens, which leads to maturation and induction of a proinflammatory state of these dendritic cells. As a consequence, they present these modified autoantigens to T cells in an immunogenic way, which become activated and stimulate autoreactive B cells to secrete autoantibodies. In this review the currently available evidence for the sequential steps in the pathogenesis of SLE is discussed. Furthermore, the mechanisms responsible for the nephritogenicity of antinucleosome antibodies are reviewed. This will reveal that nucleosomes are not only a major driving force in the formation of antinuclear antibodies, but also play a pivotal role in the development of tissue lesions by mediating binding of autoantibodies to basement membranes as exemplified for the kidney.

Anti-apoptotic Genes are Upregulated in Tolerized CD8+ Regulatory T Cells Isolated from SLE-Prone Mice (99.41)

Abstract Purpose: We studied the role of two different regulatory T cells (CD4+CD25+Foxp3+ Treg and TGFβ/IL10-secreting CD8+ Ts) in apoptosis pathways using a mouse model of systemic lupus erythematosus (SLE). Methods: Ten-week old female NZB/NZW F1 mice were tolerized with a synthetic peptide based on anti-dsDNA VH sequences (pCons) that delays SLE symptoms or isotonic saline and killed one week later (n=6/group). After Treg and Ts isolation from spleens, gene transcript levels from three different pathways - apoptosis, T cell tolerance, and TGFβ - were examined by real-time PCR-based gene arrays (SA Biosciences). These platforms contain primers for 84 pathway-specific genes. Results: Differences in Treg mRNA between the two groups were not apparent. In Ts, however, Bcl2, survivin, COX-2, Pak7, and IL-10 transcripts were significantly elevated more than two-fold in the pCons group. The proapoptotic gene Apaf1 was also significantly downregulated, implicating inhibition of specific caspases. Western blot confirmed altered protein regulation of these genes. Bcl-2, survivin and COX-2 are direct targets of the antiapoptotic transcription factor NF-κB, and Apaf-driven signaling pathways are involved in NF-κB regulation. Conclusions: Results from these experiments provide additional insights into Ts apoptosis in SLE and could lead to novel therapeutic options designed to alter Ts biology.

Up-regulation of cellular FLICE-inhibitory protein in peripheral blood B lymphocytes in patients with systemic lupus erythematosus is associated with clinical characteristics

Systemic lupus erythematosus (SLE) is an autoimmune disease which is involved in T- and B-lymphocyte-mediated autoimmunity. Apoptosis contributes to the maintenance of lymphocytes homeostasis and the deletion of autoreactive cells in SLE. Although there is evidence that cellular FLICE-inhibitory protein (c-FLIP), an antiapoptosis protein, is increased in human lupus T cells to keep them from apoptosis, but the expression of apoptosis-regulatory protein c-FLIP in SLE B lymphocytes remains unknown. To study the expression of c-FLIP in peripheral blood B lymphocytes in SLE patients and to investigate the relationship among the expression of c-FLIP in peripheral blood B lymphocytes in SLE patients, clinical manifestation and the levels of interleukin-4 (IL-4) and IL-10. In this study, we detected the expression of c-FLIP in peripheral blood B lymphocytes in SLE patients by flow cytometry and the levels of IL-4 and IL-10 in SLE serum samples by enzyme-linked immunosorbent assay and analysed their relationship with clinical characteristics. We observed a significantly higher percentage of c-FLIP in peripheral B cells in SLE patients with active disease when compared to inactive ones and healthy controls. And the expression of c-FLIP in lupus peripheral B cells showed positive correlations with SLEDAI, erythrocyte sedimentation rate, C-reactive protein, antinucleosome antibody titre, IL-4, and IL-10, and negative correlation with white blood cell count. Patients with lupus nephritis had higher levels of c-FLIP in peripheral B cells than patients without lupus nephritis. Our data show that overexpression of c-FLIP is relevant to the activity and severity of SLE. Its overexpression might play a role in preventing B cell from apoptosis in SLE. The cause of c-FLIP overexpression may be due to the increase of IL-4 and IL-10 levels in SLE patients.

Serum DNase I, soluble Fas/FasL levels and cell surface Fas expression in patients with SLE: a possible explanation for the lack of efficacy of hrDNase I treatment

The objectives of the study are to evaluate DNase I serum levels and their correlation with soluble Fas (sFas) and soluble Fas ligand (sFasL) and with cell surface Fas expression in patients with systemic lupus erythematosus (SLE), thus contributing to the dysregulated apoptosis typical of the disease. The methods include the following: Serum DNase I levels in patients and in controls were detected using the dot blot method and quantified by densitometry; sFas and sFasL were quantified using an ELISA system. Cell surface Fas expression was evaluated by FACS analysis. Apoptosis was studied by means of internucleosomal DNA degradation using a commercially available kit. The results are as follows: We found a significant difference in DNase I, sFas and sFasL serum levels between patients and controls. Levels of DNase I <7.79 ng ml(-1) are more represented in patients with SLE. Active SLE is strongly associated with high sFas levels and detectable sFasL. DNase I does not correlate with sFas or sFasL, whereas it correlates with T cell surface Fas expression that is higher in patients with active SLE than in healthy controls. Finally, administration of exogenous human recombinant DNase (hrDNase) I to freshly isolated T cells up-regulates cell surface Fas expression and induces increased susceptibility to Fas-mediated apoptosis. In conclusion, our findings confirm that DNase I is low in SLE and suggest that it may play a role in apoptosis in SLE by regulating the surface expression of the cell death molecule Fas. This role may contribute to explain the inefficacy of hrDNase I in SLE, a treatment proposed for the ability of DNase I to remove DNA from auto-antigenic nucleoprotein complexes.

Enhanced propensity of T lymphocytes in patients with systemic lupus erythematosus to apoptosis in the presence of tumour necrosis factor alpha

Objective: To determine the effect of inflammation through exposure to tumour necrosis factor (TNF)α on T lymphocytes in patients with systemic lupus erythematosus (SLE).Methods: We studied the effect of TNFα on T‐lymphocyte apoptosis in patients with SLE, rheumatoid arthritis (RA), and in healthy controls. Apoptosis of CD4 and CD8 T lymphocytes and naive and memory subpopulations was determined by flow cytometry using 7‐amino‐actinomycin D (7AAD) and propidium iodide (PI). In SLE, apoptosis was studied in patients with active and inactive disease and in patients on different medications.Results: TNFα enhanced apoptosis of anti‐CD3‐activated T lymphocytes. The percentage of apoptotic cells was significantly higher in T lymphocytes from patients with SLE than RA patients and healthy controls. After 3 days of culture, 38% of CD4+ and 37% of CD8+ cells from SLE patients underwent apoptosis in the presence of TNFα compared with 25% CD4+ and 26% CD8+ T cells from the controls (p<0.001). In healthy controls, more memory than naive T lymphocytes underwent apoptosis. By contrast, in patients with SLE, more naive T cells underwent apoptosis with TNFα (p<0.01). Enhanced apoptosis of T cells in SLE was independent of disease activity or medication. Finally, inhibition experiments showed that apoptosis in the presence of TNFα was only partly blocked with anti‐Fas ligand (FasL) antibody.Conclusions: This study demonstrates that T lymphocytes in patients with SLE are more prone to apoptosis in the presence of TNFα than T lymphocytes from healthy controls. Defects in TNFα signalling pathways rather than distribution of TNF receptors (TNFRs) probably explain the enhanced apoptosis in SLE.

Treatment with Taurine Attenuates Hepatic Apoptosis in NZB/W F1 Mice Fed with a High-Cholesterol Diet

Cholesterol-rich diets are known to cause hepatic apoptosis, which has been associated with the pathogenesis of systemic lupus erythematosus (SLE). However, the mechanisms and treatments for hepatic apoptosis in SLE are poorly understood. To clarify the effects of taurine on hepatic apoptosis in SLE, NZB/W F1 mice received control, cholesterol, and cholesterol/taurine diets. Significant reductions of caspase-3 activity, TUNEL-positive cells, and Fas- and mitochondrial- dependent apoptosis were detected in liver from the cholesterol/taurine group as compared to the cholesterol group. Moreover, significant increases of phosphorylated AKT, NF-kappaB (p65), and ERK1/2 proteins were detected in liver from the cholesterol/taurine group as compared to the cholesterol group. In contrast, a significant reduction of phosphorylated p38 protein was observed in the cholesterol/taurine group. These experimental results demonstrated positive effects of taurine against hepatic apoptosis in NZB/W F1 mice fed a high-cholesterol diet and suggested the therapeutic potential of taurine in SLE.

Innate immunity and systemic lupus erythematosus

AbstractInnate immunity is the first‐line host defence against pathogens and damaged host cells, and the major cellular components are phagocytes such as monocytes/macrophages, polymorphonuclear cells and dendritic cells. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to self‐antigens, the source of which has been suggested to be apoptotic cells. In this article, we will review studies on apoptosis in SLE and discuss the contribution of innate immunity abnormalities in the development of this condition.

Accelerated Macrophage Apoptosis Induces Autoantibody Formation and Organ Damage in Systemic Lupus Erythematosus

Increased monocyte/macrophage (Mphi) apoptosis occurs in patients with systemic lupus erythematosus (SLE) and is mediated, at least in part, by an autoreactive CD4(+) T cell subset. Furthermore, autoreactive murine CD4(+) T cells that kill syngeneic Mphi in vitro induce a lupus-like disease in vivo. However, it is unclear whether increased Mphi apoptosis in SLE per se is sufficient to accelerate/promote autoimmunity. We have investigated whether increased Mphi apoptosis in vivo, induced by the administration of clodronate liposomes, can exacerbate the autoimmune phenotype in NZB x SWR (SNF(1)) lupus-prone mice, and induce autoantibody production in haplotype-matched BALB/c x DBA1 (DBF(1)) non-lupus-prone mice. Lupus-prone mice SNF(1) mice that were treated with clodronate liposomes, but not mice treated with vehicle, developed significant increases in autoantibodies to dsDNA, nucleosomes, and the idiotypically related family of nephritic Abs Id(LN)F(1), when compared with untreated SNF(1) mice. Furthermore, clodronate treatment hastened the onset of proteinuria and worsened SNF(1) lupus nephritis. When compared with vehicle-treated controls, clodronate-treated non-lupus-prone DBF(1) mice developed significantly higher levels of anti-nucleosome and Id(LN)F(1) Abs but did not develop lupus nephritis. We propose that Mphi apoptosis contributes to the pathogenesis of autoantibody formation and organ damage through both an increase in the apoptotic load and impairment in the clearance of apoptotic material. This study suggests that mechanisms that induce scavenger cell apoptosis, such as death induced by autoreactive cytotoxic T cells observed in SLE, could play a pathogenic role and contribute to the severity of the disease.

Partial construction of apoptotic pathway in PBMC obtained from active SLE patients and the significance of plasma TNF-α on this pathway

Systemic lupus erythematosus (SLE) is a complex autoimmune disorder that affects various organs and systems. Increased apoptosis, together with defects in the uptake of apoptotic bodies, are thought to have a pathogenic role in SLE. By detection of chromatin condensation, 30% of apoptosis was detected in peripheral blood mononuclear cells (PBMC) from Thai patients with active SLE. Therefore, understanding of the molecular processes in PBMC apoptosis may allow us to gain insight into pathophysiology of SLE. Thus, genes involved in the apoptosis of PBMC from these patients were investigated ex vivo by cDNA array analysis. Seventeen apoptosis-related genes were stimulated in active SLE, more than twofold higher than in inactive SLE. These genes are classified into six groups, namely death receptors, death ligands, caspases, bcl-family, and neutral proteases and genes involved in endoplasmic reticulum stress-mediated apoptosis, such as caspase-4 and GADD153. Among those stimulated genes, tumor necrosis factor (TNF) and the TNF-receptor family were drastically up-regulated 60- and 19-fold higher than in healthy controls, respectively. Moreover, the degree of apoptosis correlated with the level of TNF-alpha in plasma, suggesting that the TNF family plays a role in the induction of apoptosis in SLE. To verify this hypothesis, PBMC from healthy individuals were treated with plasma from active SLE patients in the presence or absence of etanercept, a TNF inhibitor. In the presence of etanercept, active SLE plasma reduced the level of apoptosis to 26.43%. In conclusion, massive apoptotic death of PBMC occurred during the active stage of SLE. The molecular pathway of SLE-PBMC apoptosis was mediated at least via TNF/TNFR signaling pathway, which was confirmed by functional test of TNF-alpha in SLE patients' plasma.

Systemic lupus erythematosus and nucleosome

The property of nucleosome in systemic lupus erythematosus (SLE) is reviewed. Nucleosome, complex of histone and DNA, is thought to have a pivotal role in pathogenesis of SLE. It is formed during apoptosis that is increased in peripheral lymphocytes of SLE. The concentration of nucleosome is elevated in SLE, probably related with disease activity. Nucleosome is speculated that the clearance from peripheral blood is decreased and that is modified by viral infection to become more immunogenic. Anti-nucleosome antibody is highly positive in majority of SLE, and is very specific for SLE except scleroderma and mixed connective tissue disease. This antibody is thought as a diagnostic marker and probably an activity marker for SLE. Anti-nucleosome antibody forms immune complex with nucleosome. As histone has strong positive charge, it is demonstrated that this nucleosome/anti-nucleosome complex is bound to negatively charged heparan sulfate of glomerular basement membrane in kidney. Then, complements bind to this antibody to generate lupus glomerulonephritis. Although main site of apoptosis in SLE is considered as lymphocytes, we experienced a case with SLE who had liver dysfunction with elevated soluble Fas ligand (sFasL) and apoptosis in her hepatocytes in the active stage of SLE. We measured serum sFasL, and found the relation of sFasL and liver involvement in active SLE. As major source of nucleosome should be apoptosis of lymphocytes in SLE, hepatocytes could be another candidate of apoptosis in some SLE.

Genetic dissection of systemic autoimmune disease in Nrf2-deficient mice.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with immune-complex deposition that affects multiple organs. Previous studies have suggested the involvement of oxidative stress and apoptosis in SLE, but no clear link to etiology has been established. Here we show that mice deficient in a transcription factor responsible for controlling the expression of numerous detoxification and antioxidant genes develop an autoimmune disease with multiple organ pathologies that closely resembles human SLE. Aged female mice with a knockout of nuclear factor, erythroid-derived 2, like 2 (nrf2) are prone to develop antibodies against double-stranded DNA and the Smith antigen as well as IgG, IgM, and C3 deposition in kidney, liver, heart, and brain. Prior to the development of autoimmune antibodies and organ pathology, oxidative damage occurs in the liver and kidney as indicated by the increased levels of the DNA oxidation marker 8-hydroxydeoxyguanosine and the later increase in the lipid peroxidation product malondialdehyde. Gene expression profiles demonstrate an early decrease in numerous antioxidant and detoxification genes in the livers and altered levels of cytokines and T and B cell-specific genes in the spleens of nrf2 knockout mice. These data strongly suggest that a deficiency in detoxification and increased oxidative stress can result in the development of a systemic autoimmune disease.

Apoptosis in systemic lupus erythematosus

Apoptosis in systemic lupus erythematosus

Endothelial cell apoptosis in systemic lupus erythematosus: a common pathway for abnormal vascular function and thrombosis propensity

AbstractWomen with systemic lupus erythematosus (SLE) are at risk for premature atherothrombosis independent of Framingham risk factors. We investigated whether endothelial cell (EC) apoptosis predicts abnormal vasomotor tone and contributes to circulating tissue factor (TF) levels in this disease. Brachial artery flow-mediated dilation (FMD) and nitroglycerin-mediated dilation were determined in women with SLE, healthy control subjects, and subjects with coronary artery disease (CAD) (n = 43/group). Quantification of circulating apoptotic ECs was performed by flow cytometry (CD146+ cells that stained for Annexin V [CD146AnnV+]) and immunofluorescent microscopy. Plasma TF was measured by enzyme-linked immunosorbent assay (ELISA). Compared with healthy control and CAD subjects, patients with SLE had higher numbers of circulating CD146AnnV+ cells (10 ± 3, 18 ± 5, and 89 ± 32 cells/mL, respectively, mean ± SEM; P < .01). Increased CD146AnnV+ cells correlated strongly with abnormal vascular function (P = .037). After adjusting for known predictors of endothelial function, CD146AnnV+ was the only variable that predicted FMD (β = –4.5, P < .001). Increased CD146AnnV+ was strongly associated with elevated levels of circulating TF (r = .46, P = .002). Circulating apoptotic ECs are elevated in young women with SLE and strongly correlate with markedly abnormal vascular function and elevated TF levels. Heightened endothelial apoptosis may represent an important mechanism for development of atherothrombosis in SLE.