endothelin-1 and Lupus-Erythematosus--Systemic

Systemic lupus erythematosus (SLE) is a chronic rheumatic disorder. Endothelin-1, a vasoconstrictor, belongs to the endothelin family and is associated with vascular-related damages. To date, association between ET-1 and pathogenesis of SLE remains unclear. This case-control study was carried out by 314 SLE, 252 non-SLE diseases patients and 500 healthy controls. Serum ET-1, CCN3, IL-28B levels were detected by ELISA, and ET-1 gene polymorphisms (rs5369, rs5370, rs1476046, rs2070699, rs2071942, rs2071943, rs3087459, rs4145451, rs6458155, rs9369217) were genotyped with Kompetitive Allele-Specific PCR. SLE patients had high levels of ET-1, which were correlated with some clinical, laboratory features. Serum CCN3, IL-28B levels were higher in SLE patients, and ET-1 levels were positively correlated with the two cytokines. Rs5370, rs1476046, rs2070699, rs2071942, rs2071943, rs3087459, rs6458155 and rs2070699 were associated with SLE risk. Rs2070699 (T, TT) was related to SLE patients with alopecia. Rs5370 (T, TT, TG), rs1476046 (G,GA), rs2071942 (G,GA) and rs2071943 (G,GA) were associated with SLE patients with pericarditis, pyuria and fever manifestation, respectively. Rs3087459 (CC) and rs9369217 (TC) were related to SLE patients with positive anti-SSB antibody. Rs5369 (AA) was associated with IgG and CRP levels in SLE patients. In conclusion, elevated serum ET-1 in SLE patients may be a potential disease marker, and its gene polymorphisms were related to SLE susceptibility.

Topics: Case-Control Studies; Endothelin-1; Humans; Lupus Erythematosus, Systemic; Pericarditis

Background Endothelial dysfunction plays an important role in pathogenesis of systemic lupus erythematosus (SLE). Considering the importance of serum soluble vascular cell adhesion molecule-1 as the most abundant of the circulating adhesion molecules increased as a result of endothelial dysfunction and the role of endothelin-1 in pathophysiology of SLE, this study aimed to evaluate serum soluble vascular cell adhesion molecule-1 and endothelin-1 levels in SLE patients compared to healthy subjects. Methods In this cross-sectional study, 60 SLE patients according to the Systemic Lupus International Collaborating Clinics classification criteria for SLE and 40 age and sex-matched healthy controls were included. In patients, clinical examination was performed and SLE disease activity index was assessed. Serum endothelin-1 and soluble vascular cell adhesion molecule-1 levels were measured using ELISA kits. Results The mean ± standard deviation age of patients and controls was 31.91 ± 7.66 and 33.20 ± 10.08 years, respectively. Compared to healthy controls, serum soluble vascular cell adhesion molecule-1 (1023.8 ± 352.96 vs. 866.06 ± 109.91) and endothelin-1 (77.83 ± 16.27 vs. 54.45 ± 12.01) was significantly higher in SLE patients ( P = 0.003 and P < 0.001, respectively). The most common organs involved in patients were skin, joint and kidney. There were no significant differences in serum soluble vascular cell adhesion molecule-1 and endothelin-1 levels according to organ involvement, activity of disease and the conventional serum markers of disease activity ( P > 0.05). There was no significant correlation between disease activity, organ involvement and negative or positivity of autoantibodies as well as serum complement with endothelin-1 and vascular cell adhesion molecule-1 levels ( P > 0.05). Conclusions Although our study revealed higher serum soluble vascular cell adhesion molecule-1 and endothelin-1 levels in SLE patients compared to healthy controls, there were no significant correlations between their serum levels with organ involvement and disease activity.

Topics: Adult; Biomarkers; Case-Control Studies; Cross-Sectional Studies; Disease Progression; Endothelin-1; Female; Humans; Iran; Lupus Erythematosus, Systemic; Male; Vascular Cell Adhesion Molecule-1; Young Adult

The aim of the study was to evaluate the correlation between selected serum endothelial cell activation markers such as vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), soluble thrombomodulin (sTM), soluble E-selectin (sE-selectin), disease activity, and microvascular changes determined by nailfold capillaroscopy in patients with systemic lupus erythematosus (SLE). Serum levels of VEGF, ET-1, sTM, and sE-selectin were determined by an enzyme-linked immunosorbent assay in 80 SLE patients. The disease activity was measured with Systemic Lupus Erythematosus Disease Activity Index score. Nailfold capillaroscopy was performed in all patients. Positive correlation was found between VEGF and both ET-1 (r = 0.294, p < 0.01) and sE-selectin (r = 0.274, p < 0.05) serum levels as well as between sTM and ET-1 (r = 0.273, p < 0.05) serum concentrations. We noticed also positive correlation between VEGF (r = 0.224, p < 0.05) and ET-1 (r = 0.471, p < 0.001) serum levels and disease activity, and also between VEGF serum concentration and grade of morphological changes observed by nailfold capillaroscopy (r = 0.458, p < 0.001). There was also positive correlation between capillaroscopic score and disease activity (r = 0.339, p < 0.01). Our data suggest that correlation between VEGF and both ET-1 and E-selectin serum levels as well as between sTM and ET-1 serum concentrations may reflect their participation in the pathogenesis of SLE. VEGF seems to reflect changes in microcirculation in the course of SLE, visualised by nailfold capillaroscopy. The relationship between changes in nailfold capillaroscopy, endothelial cell activation markers, and the clinical activity of SLE points to an important role of microvascular abnormalities in the clinical manifestation of the disease.

Topics: Adult; Biomarkers; E-Selectin; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Humans; Lupus Erythematosus, Systemic; Male; Microscopic Angioscopy; Microvessels; Nails; Neovascularization, Pathologic; Severity of Illness Index; Thrombomodulin; Vascular Endothelial Growth Factor A

Chronic inflammation has been implicated in the pathology of hypertension; however, the role for specific cytokines remains unclear. We tested whether tumor necrosis factor-α blockade with etanercept (Etan) reduces mean arterial pressure in a female mouse model of systemic lupus erythematosus (SLE). SLE is a chronic inflammatory disorder with prevalent hypertension. Thirty-week-old SLE (NZBWF1) and control mice (NZW/LacJ) received Etan (0.8 mg/kg SC weekly) for 4 weeks or vehicle. Mean arterial pressure (in millimeters of mercury) was increased in SLE mice (150±5 versus 113±5 in controls; P<0.05) and was lower in Etan-treated SLE mice (132±3) but not controls (117±5). Albuminuria (in micrograms per milligram of creatinine) was elevated in SLE mice (28 742±9032 versus 1075±883; P<0.05) and was lower in Etan-treated SLE mice (8154±3899) but not control animals (783±226). Glomerulosclerosis (in percentage of glomeruli) was evident in SLE mice (2.5±1.6 versus 0.0±0.0 in controls; P<0.05) and was ameliorated in Etan-treated SLE mice (0.1±0.1). Renal cortex CD68(+) cell staining (in percentage of area) was elevated in SLE mice (4.75±0.80 versus 0.79±0.12 in controls; P<0.05) and was lower in Etan-treated SLE mice (2.28±0.32) but not controls (1.43±0.25). Renal cortex NADPH oxidase activity (relative light units per milligram of protein) was higher in SLE mice compared with controls (10 718±1276 versus 7584±229; P<0.05) and lowered in Etan-treated SLE mice (6645±490). Renal cortex nuclear factor κB (phosphorylated and nonphosphorylated) was increased in SLE mice compared with controls and lower in Etan-treated SLE mice. These data suggest that TNF-α mechanistically contributes to the development of hypertension in a chronic inflammatory disease through increased renal nuclear factor κB, oxidative stress, and inflammation.

Topics: Albuminuria; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Blood Pressure; Body Weight; Chemokine CCL2; Creatinine; Disease Models, Animal; Endothelin-1; Etanercept; Female; Glomerulosclerosis, Focal Segmental; Hypertension; Immunoglobulin G; Kidney; Kidney Cortex; Lupus Erythematosus, Systemic; Mice; Mice, Inbred Strains; NADPH Oxidases; NF-kappa B; Receptors, Tumor Necrosis Factor; Tumor Necrosis Factor-alpha

Women with systemic lupus erythematosus (SLE) exhibit a high prevalence of hypertension and renal injury. Rosiglitazone (Rosi), a peroxisome proliferator activator receptor gamma (PPARgamma) agonist, has renal protective and antihypertensive effects. We tested whether Rosi ameliorates hypertension and renal injury in a female mouse model of SLE (NZBWF1). Thirty-week-old SLE and control (NZW/LacJ) mice (n > or = 6/group) were fed Rosi (5 mg.kg(-1).day(-1) in standard chow) or standard chow for 4 wk. SLE mice had increased blood pressure (BP in mmHg) compared with controls (139 +/- 4 vs. 111 +/- 4, P < 0.05). Rosi treatment lowered BP in SLE mice (127 +/- 4, P < 0.05) but not in controls (111 +/- 4). Urinary albumin (mug/mg creatinine) was increased in SLE mice compared with controls (12,396 +/- 6,525 vs. 50 +/- 6) and reduced with Rosi treatment (148 +/- 117). Glomerulosclerosis (% of glomeruli with sclerosis) was reduced in Rosi-treated SLE mice (4.2 +/- 1.6 vs. 0.4 +/- 0.3, P < 0.05). Renal monocyte/macrophage numbers (cell number/1,320 points counted) were reduced in SLE mice treated with Rosi (32.6 +/- 11.0 vs. 10.6 +/- 3.6, P < 0.05) but unchanged in controls (3.7 +/- 1.6 vs. 3.7 +/- 2.0). Renal osteopontin expression, a cytokine-regulating macrophage recruitment, was reduced in Rosi-treated SLE mice. Urinary endothelin (in pg/mg creatinine) was increased in SLE mice compared with controls (1.9 +/- 0.59 vs. 0.6 +/- 0.04, P < 0.05) and reduced in SLE mice treated with Rosi (0.8 +/- 0.11, P < 0.05). PPARgamma protein expression in the renal cortex was significantly lower in SLE mice compared with controls and was unaffected by Rosi. These data suggest that Rosi may be an important therapeutic option for the treatment of SLE hypertension and renal injury.

Topics: Albuminuria; Animals; Antihypertensive Agents; Blood Pressure; Chemokine CCL2; Disease Models, Animal; Endothelin-1; Female; Hypertension; Kidney; Kidney Diseases; Lupus Erythematosus, Systemic; Macrophages; Mice; Monocytes; Osteopontin; PPAR gamma; RNA, Messenger; Rosiglitazone; Thiazolidinediones

Systemic lupus erythematosus (SLE) is an autoimmune disease in which immunologically mediated vascular endothelial cell activation is regarded as a potential pathophysiological mechanism of systemic organ damage. We investigated selected endothelial cell activation markers in serum of patients with SLE and their relationships with systemic organ manifestations and disease activity.. Serum levels of endothelin-1 (ET-1), soluble E-selectin, and thrombomodulin (sTM) were determined by ELISA in 76 SLE patients and in 34 healthy controls.. Higher serum concentrations of ET-1, sE-selectin (p < 0.05), and sTM (p < 0.001) were observed in SLE patients in comparison with controls. Significant differences of ET-1, (p < 0.01), sTM (p < 0.001), and sE-selectin serum concentrations (p < 0.01) were found between SLE patients with systemic involvement and controls. Patients with organ manifestations (n = 34) showed significantly higher serum levels of ET-1 than patients without systemic involvement (n = 42) (p < 0.05). Comparison between patients with active and inactive SLE according to SLE Disease Activity Index (SLEDAI) score showed significantly higher concentration of ET-1 in the sera of patients with active SLE compared with inactive patients and the controls (p < 0.001).. Our findings suggest that the elevated serum concentrations of ET-1, sTM, and sE-selectin reflect persisting endothelial cell activation in SLE, and point to an important role of ET-1 in the pathogenesis of internal organ involvement. Moreover, elevated ET-1 concentrations are related to disease activity, suggesting a key role of endothelial cell activation in systemic manifestations in SLE patients.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; E-Selectin; Endothelial Cells; Endothelin-1; Endothelium, Vascular; Female; Humans; Lupus Erythematosus, Systemic; Male; Middle Aged; Thrombomodulin