Carnosic acid reduces cytokine-induced adhesion molecules expression and monocyte adhesion to endothelial cells

Background  Expression of cell adhesion molecules on the endothelium and the attachment of monocytes to endothelium may play a major role in the early atherogenic process. Aim of the study  We investigated the effects of carnosic acid on the adhesion of U937 cells to IL-1β-treated human umbilical vein endothelial cells (HUVECs), as well as on the expression of adhesion molecules. Results  Our data showed that pretreatment with 10 and 20 μmol/l carnosic acid significantly reduced the number of U937 cells adhering to IL-1β-treated HUVECs. In addition, we found that 20 μmol/l carnosic was more effective than 10 μmol/l carnosic acid at inhibiting expression of cell adhesion molecules (ICAM-1, VCAM-1, and E-selectin), the nuclear translocation of NF-κB subunits p65 and p50, and the production of ROS in IL-1β-stimulated HUVECs. Conclusions  We conclude that carnosic acid inhibits IL-1β-induced ICAM-1, VCAM-1 and E-selectin expression in HUVECs through a mechanism that involves NFκB. We propose that the reduction in binding of human monocytic cell line U937 to IL-1β-treated HUVECs is due to the anti-inflammatory properties of carnosic acid.     

Conjugated linoleic acid isomers may diminish human macrophages adhesion to endothelial surface

Dysfunction of endothelial cells and activation of monocytes in the vascular wall are important pathogenetic factors of atherosclerosis. Conjugated linoleic acids (CLAs) can modulate the function of immune system in humans: reduce the concentration of atherogenic lipoproteins, and the intensity of inflammatory processes in the plasma. In this paper, we focus on macrophage's surface integrins (β1 integrin CD49d/CD29-(VLA4); Mac-1 as well as endothelial human vein endothelial cell (HUVEC) surface adhesins: vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1)) expression in relation to CLA isomer used during cell culture. Both CLA isomers decreased expression of VLA-4 and Mac-1 on macrophages compared with control cells (cultured with bovine serum albumine (BSA) or oxidized form of low-density lipoproteins). cis-9, trans-11 CLA isomer reduced ICAM-1 and VCAM-1 expression on the endothelium surface. Strong tendency to reduce of adhesion of macrophages to HUVEC in the cells cultured with CLA isomers was observed. The potential role of cis-9, trans-11 CLA in the reduction of adhesion of macrophages to the HUVEC – one of the important steps in the inflammatory process, can be considerate. These mechanisms may contribute to the potent anti-atherosclerotic effects of CLA in vivo.     

Conjugated linoleic acid isomers may diminish human macrophages adhesion to endothelial surface

Dysfunction of endothelial cells and activation of monocytes in the vascular wall are important pathogenetic factors of atherosclerosis. Conjugated linoleic acids (CLAs) can modulate the function of immune system in humans: reduce the concentration of atherogenic lipoproteins, and the intensity of inflammatory processes in the plasma. In this paper, we focus on macrophage's surface integrins (β1 integrin CD49d/CD29-(VLA4); Mac-1 as well as endothelial human vein endothelial cell (HUVEC) surface adhesins: vascular cell adhesion molecule-1 (VCAM-1) and intracellular cell adhesion molecule-1 (ICAM-1)) expression in relation to CLA isomer used during cell culture. Both CLA isomers decreased expression of VLA-4 and Mac-1 on macrophages compared with control cells (cultured with bovine serum albumine (BSA) or oxidized form of low-density lipoproteins). cis-9, trans-11 CLA isomer reduced ICAM-1 and VCAM-1 expression on the endothelium surface. Strong tendency to reduce of adhesion of macrophages to HUVEC in the cells cultured with CLA isomers was observed. The potential role of cis-9, trans-11 CLA in the reduction of adhesion of macrophages to the HUVEC--one of the important steps in the inflammatory process, can be considerate. These mechanisms may contribute to the potent anti-atherosclerotic effects of CLA in vivo.     

A comparison of the effects of kaempferol and quercetin on cytokine-induced pro-inflammatory status of cultured human endothelial cells

We investigated the effects of the flavonols kaempferol and quercetin on the expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), endothelial cell selectin (E-selectin), inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2), and on the activation of the signalling molecules NF-kappaB and activator protein-1 (AP-1), induced by a cytokine mixture in cultured human umbilical vein endothelial cells. Inhibition of reactive oxygen and nitrogen species generation did not differ among both flavonols at 1 micromol/l but was significantly stronger for kaempferol at 5-50 micromol/l. Supplementation with increasing concentrations of kaempferol substantially attenuated the increase induced by the cytokine mixture in VCAM-1 (10-50 micromol/l), ICAM-1 (50 micromol/l) and E-selectin (5-50 micromol/l) expression. A significantly inhibitory effect of quercetin on VCAM-1 (10-50 micromol/l), ICAM-1 (50 micromol/l) and E-selectin (50 micromol/l) expression was also observed. Expression of adhesion molecules was always more strongly inhibited in kaempferol-treated than in quercetin-treated cells. The inhibitory effect on iNOS and COX-2 protein level was stronger for quercetin at 5-50 micromol/l. The effect of kaempferol on NF-kappaB and AP-1 binding activity was weaker at high concentrations (50 micromol/l) as compared with quercetin. The present study indicates that differences exist in the modulation of pro-inflammatory genes and in the blockade of NF-kappaB and AP-1 by kaempferol and quercetin. The minor structural differences between both flavonols determine differences in their anti-inflammatory properties and in their efficiency in inhibiting signalling molecules.     

Anti-Vascular Inflammatory Effect of Ethanol Extract from Securinega suffruticosa in Human Umbilical Vein Endothelial Cells

Securiniga suffruticosa is known as a drug that has the effect of improving the blood circulation and relaxing muscles and tendons, thereby protects and strengthen kidney and spleen. Therefore, in this study, treatment of Securiniga suffruticosa showed protective effect of inhibiting the vascular inflammation in human umbilical vein endothelial cells (HUVECs) by inducing nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) coupling pathway. In this study, Securiniga suffruticosa suppressed TNF-α (Tumor necrosis factor–α) induced protein and mRNA levels of cell adhesion molecules such as intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and Interleukin-6 (IL-6). Pretreatment of HUVEC with Securiniga suffruticosa decreased the adhesion of HL-60 cells to Ox-LDL (Oxidized Low-Density-Lipoprotein)-induced HUVEC. Moreover, Securiniga suffruticosa inhibited TNF-α induced intracellular reactive oxygen species (ROS) production. Securiniga suffruticosa also inhibited phosphorylation of IκB-α in cytoplasm and translocation of NF-κB (Nuclear factor-kappa B) p65 to the nucleus. Securiniga suffruticosa increased NO production, as well increased the phosphorylation of eNOS and Akt (protein kinase B) which are related with NO production. In addition, Securiniga suffruticosa increased the protein expression of GTPCH (Guanosine triphosphate cyclohydrolase Ⅰ) and the production of BH4 in HUVEC which are related with eNOS coupling pathway. In conclusion, Securiniga suffruticosa has a protective effect against vascular inflammation and can be a potential therapeutic agent for early atherosclerosis.     

Effect of fatty acids on expression of endothelial leukocyte adhesion molecules

Summary.Background: With respect to linoleic acid both beneficial and proatherogenic effects have been described. However, the effect on expression of cell adhesion molecules on human coronary artery endothelial cells (HCAEC) is not yet established. The aim of the experiments was to evaluate the influence of linoleic acid in comparison with palmitic acid regarding the cytokine-induced expression of endothelial leukocyte adhesion molecules (intercellular cell adhesion molecule-1 ICAM-1, vascular cell adhesion molecule-1 VCAM-1, E-selectin).Methods: HCAEC were cultured in microvascular endothelial cell growth medium. In the experiments, the cells were preincubated with linoleic acid and palmitic acid, respectively (10 µmol/l, 2 days) or under control conditions, after which interleukin- 1 (IL-1, 10 ng/ml in the test medium) was added for 1 day. The monoclonal antibodies used were fluorescein isothiocyanate (FITC)- labeled anti-ICAM-1, FITC-labeled anti-VCAM-1, and FITC-labeled anti-E-selectin. Expression was analyzed by flow cytofluorimetry. Next, to examine the effects of fatty acids on adhesion of monocytes to endothelial cells, adhesion experiments with the monocytic U 937 cell line were performed.Results and conclusions: IL-1 increased ICAM-1,VCAM-1, and E-selectin expression compared to controls. Incubation with IL-1 together with linoleic acid reduced the expression of ICAM-1 and VCAM-1 in contrast to palmitic acid. Furthermore, in the presence of linoleic acid a tendency of diminished adhesion of monocytes is seen.The results indicate that a reduced expression of cell adhesion molecules may be relevant to the antiatherogenic effects of linoleic acid. This is in contrast to the properties of palmitic acid.     

The bioactive agent ergothioneine, a key component of dietary mushrooms, inhibits monocyte binding to endothelial cells characteristic of early cardiovascular disease

Regular consumption of fruits and vegetables is strongly associated with a reduced risk of cardiovascular disease (CVD). This effect occurs, in part, because of the plethora of bioactive agents in foods and their subsequent function as antioxidants. Ergothioneine (ERT), a novel antioxidant, is present in edible mushrooms and is not synthesized, but is accumulated, by humans through diet. In this study, we tested whether ERT, a bioactive agent, could interrupt pro-inflammatory induction of adhesion molecule expression associated with atherogenesis. Human aortic endothelial cells (HAECs) were incubated with increasing concentrations of ERT (0.01-10.0 mM) overnight (16 hours) followed by incubation with medium alone or with the pro-inflammatory cytokine interleukin (IL)-1β (5 ng/mL) for 6 hours to induce expression of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and endothelial-leukocyte adhesion molecule (ELAM-1 or E-selectin). ERT at 0.1-0.3 mM significantly (P 相似文献   

Vascular endothelium as a target of beraprost sodium and fenofibrate for antiatherosclerotic therapy in type 2 diabetes mellitus

Diabetes mellitus is an important risk factor for cardiovascular morbidity and mortality. The metabolic abnormalities caused by diabetes mellitus induce vascular endothelial dysfunction that predisposes patients with diabetes mellitus to atherosclerosis. Two mega clinical trials showed that intensive glycemic control does not have favorable effects on reducing macrovascular events although it demonstrated significant reductions in microvascular complications. It is becoming worthwhile to clarify the beneficial effects of tight controls on blood pressure, serum lipids, and postprandial hyperglycemia to prevent atherosclerosis in patients with type 2 diabetes mellitus. Here, we focus on vascular endothelium as a target of the prostaglandin I2 analog beraprost sodium and the peroxisome proliferators-activated receptor alpha activator fenofibrate for the prevention and treatment of atherosclerosis in patients with type 2 diabetes mellitus. Beraprost sodium lowered circulating vascular cell adhesion molecule- 1 (VCAM-1) concentration and prevented the progression of carotid atherosclerosis in type 2 diabetic patients, probably through inhibiting VCAM-1 expression in vascular endothelium. Fenofibrate up-regulated endothelial nitric oxide synthase expression, which may explain its effects to improve endothelium-dependent vasodilatation and to prevent the progression of coronary atherosclerosis. The approaches to target the molecules expressed in vascular endothelium will become important for preventing the atherosclerosis in type 2 diabetes mellitus.     

Diallyl disulfide and diallyl trisulfide suppress oxidized LDL-induced vascular cell adhesion molecule and E-selectin expression through protein kinase A- and B-dependent signaling pathways

Uptake of oxidized LDL (ox-LDL) by vascular endothelial cells is a critical step in the initiation and development of atherosclerosis. Adhesion molecules are upregulated by ox-LDL and numerous inflammatory cytokines and play a pivotal role in atherogenesis. In this study, we examined whether diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), 3 major organosulfur compounds of garlic oil, reduce adhesion molecule expression induced by ox-LDL and, if so, through what mechanism. Human umbilical vein endothelial cells were preincubated with 1 mmol/L DAS, 200 mumol/L DADS, or 100 mumol/L DATS for 16 h and then with 40 mg/L ox-LDL for an additional 24 h. ox-LDL induction of cellular and cell surface expression of E-selectin and vascular cell adhesion molecule (VCAM)-1 was suppressed by garlic allyl sulfides in the order DATS > DADS > DAS. The adhesion of HL-60 cells to endothelial cells was inhibited 27 and 33% and the production of cellular peroxides was inhibited 43 and 50% by DADS and DATS, respectively (P < 0.05). ox-LDL alone dephosphorylated protein kinase B (PKB) and cAMP responsive element binding protein (CREB); such deactivation was reversed by DADS and DATS. Electrophoretic mobility shift assay showed that the activation of CREB binding to DNA was consistent with changes in CREB phosphorylation. The protein kinase A (PKA) inhibitor H89 reversed the suppression of VCAM-1 by DADS and DATS, but the phosphoinositide 3-kinase (PI3K) inhibitor wortmannin had no effect. In contrast, wortmannin abolished DADS- and DATS-induced suppression of ox-LDL-induced E-selectin expression. These results suggest that the suppression of ox-LDL-induced E-selectin and VCAM-1 expression by DADS and DATS and, thus, monocyte adhesion to endothelial cells is likely dependent on the PI3K/PKB or PKA/CREB signaling pathway in an adhesion molecule-specific manner. To our knowledge, this is the first report that garlic modulates ox-LDL-mediated leukocyte adhesion to human endothelial cells through the PKB and PKA pathways.     

Low-calorie cranberry juice supplementation reduces plasma oxidized LDL and cell adhesion molecule concentrations in men

Elevated circulating concentrations of oxidized LDL (OxLDL) and cell adhesion molecules are considered to be relevant markers of oxidative stress and endothelial activation which are implicated in the development of CVD. On the other hand, it has been suggested that dietary flavonoid consumption may be cardioprotective through possible favourable impacts on LDL particle oxidation and endothelial activation. The present study was undertaken to determine the effect of the daily consumption of low-calorie cranberry juice cocktail on plasma OxLDL, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin concentrations in men. Thirty men (mean age 51 (sd 10) years) were recruited and asked to consume increasing daily doses of cranberry juice cocktail (125, 250 and 500 ml/d) over three successive periods of 4 weeks. Plasma OxLDL and adhesion molecule concentrations were measured by ELISA before and after each phase. We noted a significant decrease in plasma OxLDL concentrations following the intervention (P < 0.0001). We also found that plasma ICAM-1 (P < 0.0001) and VCAM-1 (P < 0.05) concentrations decreased significantly during the course of the study. In summary, the present results show that daily cranberry juice cocktail consumption is associated with decreases in plasma OxLDL, ICAM-1 and VCAM-1 concentrations in men.     

Chronic alcohol consumption increases serum levels of circulating endothelial cell/leucocyte adhesion molecules E-selectin and ICAM-1.

A group of 30 chronic alcoholics without alcohol-related diseases and 30 controls (teetotallers) were selected to measure serum levels of endothelial adhesion molecules (AMs) (ICAM-1, VCAM-1, and E-selectin). ICAM-1 and E-selectin serum levels were higher in alcoholics, whereas VCAM-1 serum levels were similar in both groups. There was a significant correlation between daily alcohol intake and serum level of ICAM-1 (r = 0.49, P = 0.003) and E-selectin (r = 0.41, P = 0.02). A significant positive correlation between E-selectin and total lifetime dose of ethanol was also observed (r = 0.52, P = 0.003). These changes in serum levels of endothelial AMs of chronic alcoholics may reflect endothelial and/or immune activation, and could interfere with the reactions between immune cells and the endothelium.     

Resveratrol blunts tumor necrosis factor-��-induced monocyte adhesion and transmigration

The leukocyte recruitment and transmigration across the endothelial barrier into the vessel wall are crucial steps in atherosclerosis. Leukocyte trafficking on the endothelium is elicited by induction of endothelial adhesion molecules, and its transmigration is mediated by degradation of basement membrane proteins through enzymatic activity of matrix metalloproteinases (MMP). The current study investigated whether resveratrol, a polyphenol present in grapes and red wine, was capable of inhibiting leukocyte adhesion to tumor necrosis factor (TNF)-α-activated endothelium. It was found that resveratrol inhibited the TNF-α-activated endothelial expression of vascular cell adhesion molecule-1 in a dose-dependent manner. In addition, resveratrol hampered THP-1 monocyte adhesion to activated endothelial cells. This study further examined whether resveratrol interfered with transendothelial migration of leukocytes. The MMP-2 gelatinolytic activity of endothelial cells was enhanced by TNF-α, which was attenuated by an addition of ≥25 µM resveratrol. In addition, 25 µM resveratrol mitigated the MMP-9 activity of THP-1 cells, followed by a marked inhibition of transendothelial migration. These results demonstrated that resveratrol suppressed monocyte adhesion and migration induced by TNF-α through modulating expression of adhesion molecules and gelatinolytic activity of MMP. These findings suggest that dietary resveratrol may be therapeutic agent for inhibiting leukocyte recruitment into the subendothelium during inflammatory atherosclerosis.     

Short-chain fatty acids modulate gene expression for vascular endothelial cell adhesion molecules

OBJECTIVE: Leukocyte infiltration into the intestinal wall is central to the pathogenesis of tissue injury that occurs in patients with a variety of inflammatory bowel diseases. Migration of leukocytes from the intestinal circulation into bowel tissues is mediated by chemotactic substances and adhesion molecules (i.e., intercellular adhesion molecule-1 [ICAM-1] and E-selectin) on the surface of endothelial cells lining blood vessels. Short-chain fatty acids (SCFAs) derived from dietary fiber decrease inflammatory responses in colon cells. However, the effect of SCFAs on vascular adhesion molecules is unknown. We investigated the effects of SCFAs on vascular endothelial cell adhesion molecule expression. METHODS: We assessed the effect of physiologically relevant concentrations of butyrate on expression of ICAM-1 protein and mRNA in cultures of human umbilical vein endothelial cells. We also assessed the effect of butyrate on levels of HLA-DR, E-selectin, vascular cell adhesion molecule-1, and endoglin. In additional experiments, we evaluated the effect of butyrate on ICAM-1 mRNA stability and the effect of valerate, isobutyrate, and propionate on ICAM-1 expression. The effect of butyrate on ICAM-1 expression was compared with that of trichostatin A, a specific inhibitor of histone deacetylase. Data were evaluated with Student's t tests or Tukey's multiple comparison tests, with P < 0.05 considered statistically significant. RESULTS: Butyrate concentrations of 2.5 to 5 mM significantly increased endothelial expressions of ICAM-1 protein and mRNA. The effect of butyrate (5 mM) on ICAM-1 expression was time dependent, with significant increases in levels occurring after 16 h of incubation. Butyrate (5 mM) also increased expression of E-selectin but not of HLA-DR, vascular cell adhesion molecule-1, or endoglin. Isobutyrate had little effect on ICAM-1 expression, whereas valerate and propionate significantly increased expression of ICAM-1 but were weaker stimulants compared with butyrate. Butyrate (5 mM) did not alter stability of ICAM-1 mRNA. The effect of butyrate (5 mM) was comparable to that of trichostatin A. The stimulatory effect of butyrate on ICAM-1 expression was reversed after 48 h of butyrate withdrawal. CONCLUSIONS: Butyrate increases vascular endothelial expressions of ICAM-1 and E-selectin. We speculate that butyrate-induced effects on vascular adhesion molecules modulate gut inflammation. The role of SCFAs and fiber in the pathogenesis and modulation of gut inflammation in vivo requires further study.     

新疆传统发酵乳酪中乳清对动脉粥样硬化兔VCAM-1、ICAM-1和CRP的影响

目的观察哈萨克族传统发酵乳酪乳清(乳清,TFCW)对实验性动脉粥样硬化(AS)兔C-反应蛋白(CRP)、血管细胞黏附分子-1(VCAM-1)及细胞间黏附分子(ICAM-1)的影响。方法通过喂高脂饲料,建立AS新西兰兔模型。高脂饮食8 w后给予TFCW(25、50mg/kg)及阳性对照药辛伐他汀(simvastatin),给药4 w后,分别测定血脂、C-反应蛋白(CRP)、VCAM-1和ICAM-1水平和肝指数;观察干预后组织病理变化,同时应用免疫组化方法检测VCAM-1及ICAM表达。结果 TFCW 25、50 mg/kg均可降低AS兔血清总胆固醇(TC,P<0.05),低密度脂蛋白胆固醇(LDL-C)水平(P<0.01),升高高密度脂蛋白胆固醇(HDL-C)水平,显著降低CRP(P<0.01)及VCAM-1和ICAM-1水平。光镜下和肉眼都可见到TFCW 25mg/kg组出现AS斑块。TFCW 50mg/kg组出现少量AS斑块。VCAM-1在正常状态下呈低表达,MC组胸主动脉组有VCAM-1高表达。TFCW 25、50mg/kg组VCAM-1表达减少。结论 TFCW 25、50mg/kg组具有调节血脂及减少粘附分子表达,提示TFCW抗实验性AS作用与其内皮保护作用及抗炎作用有关。     

Association between arsenic exposure from drinking water and plasma levels of cardiovascular markers

The authors conducted a cross-sectional study to assess the relation between arsenic exposure from drinking water and plasma levels of markers of systemic inflammation and endothelial dysfunction (matrix metalloproteinase-9, myeloperoxidase, plasminogen activator inhibitor-1, soluble E-selectin, soluble intercellular adhesion molecule-1 (ICAM-1), and soluble vascular adhesion molecule-1 (VCAM-1)) using baseline data from 668 participants (age, >30 years) in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2007-2008). Both well water arsenic and urinary arsenic were positively associated with plasma levels of soluble VCAM-1. For every 1-unit increase in log-transformed well water arsenic (ln μg/L) and urinary arsenic (ln μg/g creatinine), plasma soluble VCAM-1 was 1.02 (95% confidence interval: 1.01, 1.03) and 1.04 (95% confidence interval: 1.01, 1.07) times greater, respectively. There was a significant interaction between arsenic exposure and higher body mass index, such that the increased levels of plasminogen activator inhibitor-1 and soluble VCAM-1 associated with arsenic exposure were stronger among people with higher body mass index. The findings indicate an effect of chronic arsenic exposure from drinking water on vascular inflammation and endothelial dysfunction that could be modified by body mass index and also suggest a potential mechanism underlying the association between arsenic exposure and cardiovascular disease.