Salvianolic acid B protects human endothelial progenitor cells against oxidative stress-mediated dysfunction by modulating Akt/mTOR/4EBP1, p38 MAPK/ATF2, and ERK1/2 signaling pathways

The vascular endothelium is specifically sensitive to oxidative stress, and this is one of the mechanisms that causes widespread endothelial dysfunction in most cardiovascular diseases and disorders. Protection against reactive oxygen species (ROS)-mediated oxidative damage via antioxidant mechanisms is essential for tissue maintenance and shows therapeutic potential for patients suffering from cardiovascular and metabolic disorders. Salvianolic acid B (SalB), a natural bioactive component known from Traditional Chinese Medicine, has been reported to exert cellular protection in various types of cells. However, the underlying mechanisms involved are not fully understood. Here, we showed that SalB significantly promoted the migratory and tube formation abilities of human bone marrow derived-endothelial progenitor cells (BM-EPCs) in vitro, and substantially abrogated hydrogen peroxide (H₂O₂)-induced cell damage. SalB down-regulated Nox4 and eNOS, as well as nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase expression upon H₂O₂ induction that in turn prevents oxidative-induced endothelial dysfunction. Moreover, SalB suppressed the Bax/Bcl-xL ratio and caspase-3 activation after H₂O₂ induction. Furthermore, our results provide mechanistic evidence that activation of the mTOR/p70S6K/4EBP1 pathways is required for both SalB-mediated angiogenic and protective effects against oxidative stress-induced cell injury in BM-EPCs. Suppression of MKK3/6-p38 MAPK-ATF2 and ERK1/2 signaling pathways by SalB significantly protected BM-EPCs against cell injury caused by oxidative stress via reduction of intracellular ROS levels and apoptosis. Taken together, by providing a mechanistic insight into the modulation of redox states in BM-EPCs by SalB, we suggest that SalB has a strong potential of being a new proangiogenic and cytoprotective therapeutic agent with applications in the field of endothelial injury-mediated vascular diseases.     

妊高症患者及新生儿脐血VE-cadherin和HMGB1的检测

目的分析妊高症患者及新生儿脐血血清血管内皮细胞钙黏蛋白（VE-cadherin）和高迁移率蛋白-1（HMGB1）的变化。方法采用酶联免疫吸附法（ELISA）测定98例妊高症患者（包括妊娠期高血压40例、轻度子痫前期30例和重度子痫前期28例）及30例正常对照组产妇及新生儿脐血血清VE-cadherin和HMGB1含量。结果VE-cad herin和HMGB1在妊高症组及正常对照组及新生儿脐血血清中均有表达,VE-cadherin在三组妊高症病患者血清中含量与正常对照组比较,差异有显著意义（t=5.83,8.41,9.04,P均〈0.05）。随着病情越严重,VE-cadherin水平越高,三组之间差异有统计学意义（t=6.23,8.56,P均〈0.05）;HMGB1与VE-cadherin分布高度一致,并呈正相关（r=0.59,P〈0.01）。VE-cadherin和HMGB1在妊高症各组新生儿脐血中的含量,差异无统计学意义（P〉0.05）。结论VE-cadherin和HMGB1的高表达,显示妊高症病患者内皮细胞损伤,是妊高症内皮损伤炎症标记物,为妊高症的治疗和预防开辟一条新途径     

新诊断2型糖尿病血清VE-Ca与颈动脉粥样硬化的相关性

目的探讨2型糖尿病患者血清血管内皮钙粘蛋白(VE-cadherin,VE-Ca)水平与血糖、血脂及2型糖尿病早期颈动脉粥样硬化(CAS)的关系。方法将新诊断T2DM患者90例,根据有无CAS分为合并CAS组(A组)48例和无CAS组(B组)42例,设健康对照组(C组)35例。测量体重指数、血压,检测临床生化指标和血清VE-Ca水平。结果3组血清VE-Ca水平依次为:C组(2.79±1.68)ng/mLB组(4.53±1.42)ng/mLA组(5.16±1.43)ng/mL,3组比较,差异有统计学意义(P0.05或P0.01)。血清VE-Ca与FPG、HbA1c、TG、SBP、DBP显著正相关(r分别为0.237、0.734、0.319、0.229、0.349,P0.01)。经Logistic回归分析显示,VE-Ca、DBP、FPG、TC是T2DM发生CAS的主要影响因素。结论血清VE-Ca在新诊断T2DM合并颈动脉斑块人群中升高,在新诊断T2DM合并CAS的发生中起重要作用。     

Effect of hormone therapy and raloxifene on serum VE-cadherin in postmenopausal women

OBJECTIVE: To investigate the effect of continuous combined hormone therapy and raloxifene on serum VE-cadherin. DESIGN: The study was double blinded, with a placebo run-in period of 28-50 days. SETTING: University menopause clinic. PATIENT(S): Twenty-eight healthy postmenopausal women devoid of climacteric complaints. INTERVENTION(S): Subjects were randomized to 17beta-estradiol (2 mg) + norethisterone acetate (1 mg; E(2)-NETA) or raloxifene hCL (60 mg) for a period of 6 months. MAIN OUTCOME MEASURE(S): Serum VE-cadherin, which was estimated at baseline and at month 6. RESULT(S): Serum VE-cadherin decreased significantly in both E(2)-NETA and raloxifene groups (raloxifene baseline +/- SD: 1.17 +/- 0.44 ng/mL, 6 months: 0.82 +/- 0.29 ng/mL; E(2)-NETA baseline: 1.19 +/- 0.47 ng/mL, 6 months: 0.92 +/- 0.49 ng/mL). Percentage changes from baseline were -21.7 +/- 24.3 for E(2)-NETA and -26.0 +/- 20.6 for raloxifene. CONCLUSION(S): The effect of E(2)-NETA and raloxifene suggests that these drugs may preserve interendothelial junction integrity and control vascular permeability. Although this effect may influence the progress of the atheromatous lesion, its clinical impact on coronary artery disease (CAD) remains uncertain.     

Confocal immunolocalization of VE-cadherin- and CXC chemokine-expressing endothelial cells in periapical granulomas

Aim To determine whether endothelial cells (ECs) in periapical granulomas can express vascular endothelial (VE)‐cadherin, CXCL8 and CXCL10 by examining with two‐colour confocal laser scanning microscope. Methodology Periapical lesions were surgically removed from patients with chronic periapical periodontitis (n = 20), and the paraffin‐embedded sections were prepared after being fixed with cold acetone. The 7‐μm‐thick sections were stained with haematoxylin–eosin and then examined pathologically using a light microscope. The lesions diagnosed as periapical granulomas (17 specimens) were analysed further using immunofluorescence and antibodies specific for human VE‐cadherin, CXCL8, and CXCL10. The slides were carefully examined using a confocal laser scanning microscope. The numbers of positive ECs were counted, and the comparison between VE‐cadherin‐positive ECs and CXCL8 or CXCL10 was assessed statistically using one‐way ANOVA followed by a Student–Newman–Keuls test. Results The expression of CXCL8 and CXCL10 by ECs was detected in 60.4 ± 13.4 and 67.2 ± 13.9%, respectively. However, the percentage of VE‐cadherin‐expressing ECs was 40.4 ± 10.5%, which was significantly lower (P < 0.01) than CXCL8 and CXCL10‐expressing ECs. Two‐colour immunofluorescence staining revealed that ECs co‐expressed VE‐cadherin and CXCL8 (37.4 ± 14.1%) or CXCL10 (39.1 ± 13.8%). Conclusions VE‐cadherin expression in ECs was lower than CXCL8 and CXCL10, suggesting that inflamed ECs in periapical granulomas could increase vascular permeability and that leukocyte chemotaxis mediated by ECs might occur. These findings may suggest the possibility that ECs could play a pivotal role in cell recruitment in periapical granulomas.     

糖尿病大鼠视网膜黏附连接蛋白表达的变化

目的:探讨链脲佐菌素(streptozotocin,STZ)诱导的糖尿病视网膜黏附连接VE-cadherin和β-catenin的表达。方法:SD大鼠50只,随机分为正常对照组(Con)、糖尿病组(DM)。腹腔注射STZ建立DM模型,2,5,8wk处死动物。用伊凡思蓝方法检测视网膜的渗透性;用免疫组织化学和Western blot方法检测各组大鼠视网膜VE-cadherin和β-catenin的表达情况。结果:造模后2,5,8wk大鼠视网膜血管渗透性增加。免疫组化分析证实DM大鼠视网膜VE-cadherin主要表达在视网膜血管上,β-catetin主要表达在视网膜外界膜、外核层、外网状层、内网状层和内界膜。Western blot分析证明随着DM视网膜病变的发生发展,视网膜VE-cadherin表达量显著减少,2,5,8wk组与Con组两两比较均有差异(P<0.05);而β-catetin表达量显著增加,2,5,8wk组与Con组两两比较差异有统计学意义(P<0.05)。结论:STZ诱导的DM大鼠VE-cadherin表达量减少而β-catetin表达量显著增加,两者成反比。     

Antepartum and postpartum maternal plasma levels of E-selectin and VE-cadherin in preeclampsia,gestational proteinuria and gestational hypertension

Objective.?To investigate the alterations of maternal antepartum and postpartum plasma levels of sE-selectin and VE-cadherin in normotensive pregnant women, women with preeclampsia (PE), gestational hypertension (GH), and gestational proteinuria (GP).

Methods.?A total of 37 pregnant women were included in the present study; 12 with PE, 10 with GH, 5 with GP, and 10 controls. sE-selectin and VE-cadherin levels were assessed in maternal plasma at three periods; before delivery, 3–6 days after delivery, and 12–14 weeks postpartum.

Results.?Women with severe preeclampsia (SPE) and GP had significantly higher plasma sE-selectin levels as compared to controls in all three periods of sampling. In the GH group, sE-selectin levels did not differ from controls. During the study, even after 12 weeks postpartum, the plasma sE-selectin levels remained unchanged in all preeclamptic groups (PE, GH, and GP). There was no difference in VE-cadherin levels between women with preeclampsia (PE, GH, and GP) and normal pregnancies.

Conclusions.?We found no changes in VE-cadherin levels in preeclamptic groups. Increased antepartum and postpartum levels of sE-selectin in women with SPE and GP suggest that endothelial dysfunction may be one of the key processes in the pathogenesis of PE and the underlying mechanism, as well, that links PE with cardiovascular disease in later life. GP, also, appears to be a mild variant of PE.     

新诊断2型糖尿病患者血清血管内皮细胞钙粘蛋白的变化及其意义

目的观察新诊断2型糖尿病患者血清血管内皮细胞钙粘蛋白等指标的变化。方法选择35例新诊断2型糖尿病患者为观察组,36例正常体检者为健康对照组。测定血清中血管内皮功能指标：血管内皮细胞钙粘蛋白（VE-cadherin）、内皮素（ET-1）、一氧化氮（NO）及一氧化氮合酶（NOS）。并同时测定空腹血糖（FBG）、餐后2 h血糖（P2hBG）、糖化血红蛋白（HbA1c）、体重指数（BMI）、血脂、收缩压（SBP）、舒张压（DBP）。结果糖尿病组血管内皮细胞钙粘蛋白水平高于健康对照组,一氧化氮低于健康对照组,差异有统计学意义（P〈0.05）。相关分析显示,血管内皮细胞钙粘蛋白与糖化血红蛋白呈正相关,一氧化氮与糖化血红蛋白呈负相关,一氧化氮和一氧化氮合酶呈正相关,一氧化氮合酶和内皮素呈负相关。结论新诊断2型糖尿病患者血管内皮功能已受损,炎症、血管内皮细胞钙粘蛋白复合体和一氧化氮途径较早受损可能共同介导糖尿病内皮功能损伤。     

急性脑梗死患者颈动脉内膜中层厚度与血清VE—cadherin和脂联素水平变化

目的探讨急性脑梗死患者颈总动脉平均内膜中层厚度（IMT）与血清血管内皮细胞钙黏蛋白（VE—cadherin）、脂联素（APN）的含量变化,及其在急性脑梗死发生过程中的作用和意义。方法采用高分辨率彩色超声诊断仪测量颈动脉IMT,并采用酶联免疫法测定血清VE-cadherin和APN水平,并与60例年龄和性别相当的健康体检者（对照组）进行比较。结果①急性脑梗死患者颈动脉IMT和血清VE-cadherin含量较两对照组显著升高,脂联素含量较对照组显著降低;②急性脑梗死患者颈动脉IMT和血清VE-cadherin、脂联素含量之间存在相关性。结论监测患者颈动脉IMT和血清VE-cadherin、脂联素含量变化有助于预测脑梗死的发生。