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Sample records for electronegative ldl inhibit

  1. A nanoformulation containing a scFv reactive to electronegative LDL inhibits atherosclerosis in LDL receptor knockout mice.

    PubMed

    Cavalcante, Marcela Frota; Kazuma, Soraya Megumi; Bender, Eduardo André; Adorne, Márcia Duarte; Ullian, Mayara; Veras, Mariana Matera; Saldiva, Paulo Hilário Nascimento; Maranhão, Andrea Queiroz; Guterres, Silvia Stanisçuaski; Pohlmann, Adriana Raffin; Abdalla, Dulcineia Saes Parra

    2016-10-01

    Atherosclerosis is a chronic inflammatory disease responsible for the majority of cases of myocardial infarction and ischemic stroke. The electronegative low-density lipoprotein, a modified subfraction of native LDL, is pro-inflammatory and plays an important role in atherogenesis. To investigate the effects of a nanoformulation (scFv anti-LDL(-)-MCMN-Zn) containing a scFv reactive to LDL(-) on the inhibition of atherosclerosis, its toxicity was evaluated in vitro and in vivo and further it was also administered weekly to LDL receptor knockout mice. The scFv anti-LDL(-)-MCMN-Zn nanoformulation did not induce cell death in RAW 264.7 macrophages and HUVECs. The 5mg/kg dose of scFv anti-LDL(-)-MCMN-Zn did not cause any typical signs of toxicity and it was chosen for the evaluation of its atheroprotective effect in Ldlr(-/-) mice. This nanoformulation significantly decreased the atherosclerotic lesion area at the aortic sinus, compared with that in untreated mice. In addition, the Il1b mRNA expression and CD14 protein expression were downregulated in the atherosclerotic lesions at the aortic arch of Ldlr(-/-) mice treated with scFv anti-LDL(-)-MCMN-Zn. Thus, the scFv anti-LDL(-)-MCMN-Zn nanoformulation inhibited the progression of atherosclerotic lesions, indicating its potential use in a future therapeutic strategy for atherosclerosis. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Increased inflammatory effect of electronegative LDL and decreased protection by HDL in type 2 diabetic patients.

    PubMed

    Estruch, Montserrat; Miñambres, Inka; Sanchez-Quesada, Jose Luis; Soler, Marta; Pérez, Antonio; Ordoñez-Llanos, Jordi; Benitez, Sonia

    2017-10-01

    Type 2 diabetic patients have an increased proportion of electronegative low-density lipoprotein (LDL(-)), an inflammatory LDL subfraction present in blood, and dysfunctional high-density lipoprotein (HDL). We aimed at examining the inflammatory effect of LDL(-) on monocytes and the counteracting effect of HDL in the context of type 2 diabetes. This was a cross-sectional study in which the population comprised 3 groups (n = 12 in each group): type 2 diabetic patients with good glycaemic control (GC-T2DM patients), type 2 diabetic patients with poor glycaemic control (PC-T2DM), and a control group. Total LDL, HDL, and monocytes were isolated from plasma of these subjects. LDL(-) was isolated from total LDL by anion-exchange chromatography. LDL(-) from the three groups of subjects was added to monocytes in the presence or absence of HDL, and cytokines released by monocytes were quantified by ELISA. LDL(-) proportion and plasma inflammatory markers were increased in PC-T2DM patients. LDL(-) from PC-T2DM patients induced the highest IL1β, IL6, and IL10 release in monocytes compared to LDL(-) from GC-T2DM and healthy subjects, and presented the highest content of non-esterified fatty acids (NEFA). In turn, HDL from PC-T2DM patients showed the lowest ability to inhibit LDL(-)-induced cytokine release in parallel to an impaired ability to decrease NEFA content in LDL(-). Our findings show an imbalance in the pro- and anti-inflammatory effects of lipoproteins from T2DM patients, particularly in PC-T2DM. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Sesamol reduces the atherogenicity of electronegative L5 LDL in vivo and in vitro.

    PubMed

    Chen, Wei-Yu; Chen, Fang-Yu; Lee, An-Sheng; Ting, Kuan-Hsiang; Chang, Chia-Ming; Hsu, Jing-Fang; Lee, Wei-Shine; Sheu, Joen-Rong; Chen, Chu-Huang; Shen, Ming-Yi

    2015-02-27

    Highly electronegative low-density lipoprotein (LDL) L5 induces endothelial cell (EC) apoptosis, which leads to the development of atherosclerosis. We examined the effects of sesamol (1), a natural organic component of sesame oil, on plasma L5 levels and atherosclerosis development in a rodent model and on the L5-induced apoptosis of ECs. Syrian hamsters, which have an LDL profile similar to that of humans, were fed a normal chow diet (control), a high-fat diet (HFD), or a HFD supplemented with the administration of 50 or 100 mg/kg of 1 via oral gavage (HFD+1) for 16 weeks (n = 8 per group). Hamsters in the HFD+1 groups had reduced plasma L5 levels when compared with the HFD group. Oil Red O staining showed that atherosclerotic lesion size was markedly reduced in the aortic arch of hamsters in the HFD+1 groups when compared with that in the HFD group. In human aortic ECs, 0.3-3 μM 1 blocked L5-induced apoptosis in a dose-dependent manner. Further mechanistic studies showed that 1 inhibited the L5-induced lectin-like oxidized LDL receptor-1 (LOX-1)-dependent phosphorylation of p38 MAPK and activation of caspase-3 and increased phosphorylation of eNOS and Akt. Our findings suggest that sesamol (1) protects against atherosclerosis by reducing L5-induced atherogenicity.

  4. LDL phospholipid hydrolysis produces modified electronegative particles with an unfolded apoB-100 protein

    PubMed Central

    Asatryan, Liana; Hamilton, Ryan T.; Isas, J. Mario; Hwang, Juliana; Kayed, Rakez; Sevanian, Alex

    2012-01-01

    Electronegative low density lipoprotein (LDL− formation that structurally resembles LDL− isolated from plasma was evaluated after LDL treatment with snake venom phospholipase A2 (PLA2). PLA2 treatment of LDL increased its electrophoretic mobility in proportion to the amount of LDL− formed without evidence of lipid peroxidation. These changes dose-dependently correlated with the degree of phospholipid hydrolysis. Strong immunoreactivity of LDL− subfraction from plasma and PLA2-treated LDL (PLA2-LDL) to amyloid oligomer-specific antibody was observed. Higher β-strand structural content and unfolding proportionate to the loss of α-helical structure of apolipoprotein B-100 (apoB-100) of LDL− isolated from both native and PLA2-LDLs was demonstrated by circular dichroism (CD) spectropolarimetry. These structural changes resembled the characteristics of some oxidatively modified LDLs and soluble oligomeric aggregates of amyloidogenic proteins. PLA2-LDL was also more susceptible to nitration by peroxynitrite, likely because of exposure of otherwise inaccessible hydrophilic and hydrophobic domains arising from apoB-100 unfolding. This was also demonstrated for plasma LDL−. In contrast, PLA2-LDL was more resistant to copper-mediated oxidation that was reversed upon the addition of small amounts of unsaturated fatty acids. PMID:15489541

  5. Electronegative LDL-mediated cardiac electrical remodeling in a rat model of chronic kidney disease

    PubMed Central

    Lee, An-Sheng; Chen, Wei-Yu; Chan, Hua-Chen; Chung, Ching-Hu; Peng, Hsien-Yu; Chang, Chia-Ming; Su, Ming-Jai; Chen, Chu-Huang; Chang, Kuan-Cheng

    2017-01-01

    The mechanisms underlying chronic kidney disease (CKD)–associated higher risks for life-threatening ventricular tachyarrhythmias remain poorly understood. In rats subjected to unilateral nephrectomy (UNx), we examined cardiac electrophysiological remodeling and relevant mechanisms predisposing to ventricular arrhythmias. Adult male Sprague-Dawley rats underwent UNx (n = 6) or sham (n = 6) operations. Eight weeks later, the UNx group had higher serum blood urea nitrogen and creatinine levels and a longer electrocardiographic QTc interval than did the sham group. Patch-clamp studies revealed epicardial (EPI)-predominant prolongation of the action potential duration (APD) at 50% and 90% repolarization in UNx EPI cardiomyocytes compared to sham EPI cardiomyocytes. A significant reduction of the transient outward potassium current (Ito) in EPI but not in endocardial (ENDO) cardiomyocytes of UNx rats led to a decreased transmural gradient of Ito. The reduction of Ito currents in UNx EPI cardiomyocytes was secondary to downregulation of KChIP2 but not Kv4.2, Kv4.3, and Kv1.4 protein expression. Incubation of plasma electronegative low-density lipoprotein (LDL) from UNx rats with normal EPI and ENDO cardiomyocytes recapitulated the electrophysiological phenotype of UNx rats. In conclusion, CKD disrupts the physiological transmural gradient of Ito via downregulation of KChIP2 proteins in the EPI region, which may promote susceptibility to ventricular tachyarrhythmias. Electronegative LDL may underlie downregulation of KChIP2 in CKD. PMID:28094801

  6. Electronegative LDL is linked to high-fat, high-cholesterol diet-induced nonalcoholic steatohepatitis in hamsters.

    PubMed

    Lai, Yu-Sheng; Yang, Tzu-Ching; Chang, Po-Yuan; Chang, Shwu-Fen; Ho, Shu-Li; Chen, Hui-Ling; Lu, Shao-Chun

    2016-04-01

    The pathogenesis of nonalcoholic steatohepatitis (NASH), like that of atherosclerosis, involves lipid accumulation, inflammation and fibrosis. Recent studies suggest that oxidized LDL (oxLDL) may be a risk factor for NASH, but oxLDL levels were not directly measured in these studies. The aim of this study was to examine whether there was an association between electronegative LDL [LDL(-)], a mildly oxLDL found in the blood, and the development of NASH using two animal models. Golden Syrian hamsters and C57BL/6 mice were fed a high-fat, high-cholesterol (HFC) diet for 6 or 12weeks, then liver lipid and histopathology, plasma lipoprotein profile and LDL(-) levels were examined. The HFC-diet-fed hamsters and mice had similar levels of hepatic lipid but different histopathological changes, with microvesicular steatosis, hepatocellular hypertrophy, inflammation and bridging fibrosis in the hamsters, but only in mild steatohepatitis with low inflammatory cell infiltration in the mice. It also resulted in a significant increase in plasma levels of LDL cholesterol and LDL(-) in hamsters, but only a slight increase in mice. Moreover, enlarged Kupffer cells, LDL(-) and accumulation of unesterified cholesterol were detected in the portal area of HFC-diet-fed hamsters, but not HFC-diet-fed mice. An in vitro study showed that LDL(-) from HFC-diet-fed hamsters induced TNF-α secretion in rat Kupffer cell through a LOX-1-dependent pathway. Our results strongly suggest that LDL(-) is one of the underlying causes of hepatic inflammation and plays a critical role in the development of NASH. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Hibiscus anthocyanins-rich extract inhibited LDL oxidation and oxLDL-mediated macrophages apoptosis.

    PubMed

    Chang, Yun-Ching; Huang, Kai-Xun; Huang, An-Chung; Ho, Yung-Chyuan; Wang, Chau-Jong

    2006-07-01

    The oxidative modification of low-density lipoprotein (LDL) plays a key role in the pathogenesis of atherosclerosis. Anti-oxidative reagents, which can effectively inhibit LDL oxidation, may prevent atherosclerosis via reducing early atherogenesis, and slowing down the progression to advance stages. As shown in previous studies Hibiscus sabdariffa L. is a natural plant containing a lot of pigments that was found to possess anti-oxidative of activity. Therefore, in this study, we evaluated the anti-oxidative activity of Hibiscus anthocyanins (HAs) by measuring their effects on LDL oxidation (in cell-free system) and anti-apoptotic abilities (in RAW264.7 cells). HAs have been tested in vitro examining their relative electrophoretic mobility (REM), Apo B fragmentation, thiobarbituric acid relative substances (TBARS) and radical 1,1-diphenyl-2-picrylhydrazyl (DPPH) scavenging activity assay. The anti-oxidative activity of HAs was defined by relative electrophoretic mobility of oxLDL (decrease of 50% at 2 mg/ml), fragmentation of Apo B (inhibition of 61% at 1mg/ml), and TBARS assay (IC(50): 0.46 mg/ml) in the Cu(2+)-mediated oxidize LDL. Furthermore, the addition of >0.1 mg/ml of HAs could scavenge over 95% of free DPPH radicals, HAs showed strong potential in inhibiting LDL oxidation induced by copper. In addition, to determine whether oxLDL-induced apoptosis in macrophages is inhibited by HAs, we studied the viability, morphology and caspase-3 expression of RAW 264.7 cells. MTT assay, Leukostate staining analysis and Western blotting reveals that HAs could inhibit oxLDL-induced apoptosis. According to these findings, we suggest that HAs may be used to inhibit LDL oxidation and oxLDL-mediated macrophage apoptosis, serving as a chemopreventive agent. However, further investigations into the specificity and mechanism(s) of HAs are needed.

  8. Cranberries inhibit LDL oxidation and induce LDL receptor expression in hepatocytes.

    PubMed

    Chu, Yi-Fang; Liu, Rui Hai

    2005-08-26

    Cardiovascular disease (CVD) is the leading cause of death in most industrialized countries. Cranberries were evaluated for their potential roles in dietary prevention of CVD. Cranberry extracts were found to have potent antioxidant capacity preventing in vitro LDL oxidation with increasing delay and suppression of LDL oxidation in a dose-dependent manner. The antioxidant activity of 100 g cranberries against LDL oxidation was equivalent to 1000 mg vitamin C or 3700 mg vitamin E. Cranberry extracts also significantly induced expression of hepatic LDL receptors and increased intracellular uptake of cholesterol in HepG2 cells in vitro in a dose-dependent manner. This suggests that cranberries could enhance clearance of excessive plasma cholesterol in circulation. We propose that additive or synergistic effects of phytochemicals in cranberries are responsible for the inhibition of LDL oxidation, the induced expression of LDL receptors, and the increased uptake of cholesterol in hepatocytes.

  9. Novel low-density lipoprotein (LDL) oxidation model: antioxidant capacity for the inhibition of LDL oxidation.

    PubMed

    Chu, Yi-Fang; Liu, Rui Hai

    2004-11-03

    A novel model of peroxyl radical initiated low-density lipoprotein (LDL) oxidation (LDL oxidation model for antioxidant capacity, or LOMAC) was developed to assess the free radical scavenging capacity of antioxidants and the extracts of natural products. A water-soluble free radical initiator, 2,2'-azobis(amidinopropane) dihydrochloride, was used at physiological temperature (37 degrees C) to generate peroxyl radicals to catalyze lipid oxidation of LDL isolated from human plasma samples. Headspace hexanal, a major decomposition product of LDL oxidation, was measured by a headspace gas chromatograph as an indicator of antioxidant capacity of different concentrations of pure antioxidants (vitamins C and E) and the extracts of natural products (fresh apple phytochemical extracts). All vitamin C and E and apple extract concentrations tested resulted in increasing partial suppression and delay of LDL oxidation. On the basis of the median effective dose (EC(50)) calculated for each compound or extract tested, the LOMAC value of 100 g of apple against LDL oxidation was equivalent to 1470 mg of vitamin E or to 402 mg of vitamin C. This study shows that the LOMAC assay can be routinely used to analyze or screen antioxidants or phytochemical extracts against LDL oxidation to prevent cardiovascular disease. The food-specific LOMAC values will be very useful as a new alternative biomarker for future epidemiological studies of cardiovascular disease.

  10. Electronegative gases

    SciTech Connect

    Christophorou, L.G.

    1981-01-01

    Recent knowledge on electronegative gases essential for the effective control of the number densities of free electrons in electrically stressed gases is highlighted. This knowledge aided the discovery of new gas dielectrics and the tailoring of gas dielectric mixtures. The role of electron attachment in the choice of unitary gas dielectrics or electronegative components in dielectric gas mixtures, and the role of electron scattering at low energies in the choice of buffer gases for such mixtures is outlined.

  11. Apple peel bioactive rich extracts effectively inhibit in vitro human LDL cholesterol oxidation.

    PubMed

    Thilakarathna, Surangi H; Rupasinghe, H P Vasantha; Needs, Paul W

    2013-05-01

    Apple peels are rich in antioxidant bioactives and hence can possess the ability to inhibit human low density lipoprotein cholesterol (LDL-C) oxidation. LDL-C oxidation is known to initiate atherosclerotic plaque formation. Unique quercetin-rich (QAE) and triterpene-rich (TAE) apple peel extracts, their constituent compounds and three in vivo quercetin metabolites were investigated for in vitro LDL-C oxidation inhibition. Both extracts effectively inhibited Cu(2+)-induced LDL-C oxidation. IC(50) of QAE and TAE for LDL-C oxidation products were 0.06-8.29 mg/L and 29.58-95.49 mg/L, respectively. Quercetin compounds, chlorogenic acid and phloridzin could contribute more to the effectiveness of QAE at physiological concentrations. The three in vivo quercetin metabolites; quercetin-3'-sulfate, quercetin-3-glucuronic acid and isorhamnetin-3-glucuronic acid were effective at physiological concentrations and therefore, QAE can be effective in LDL-C oxidation inhibition under physiological conditions. Constituent TAE compounds did not perform well under Cu(2+)-induction. Overall, both extracts effectively inhibited LDL-C oxidation in vitro. Copyright © 2012 Elsevier Ltd. All rights reserved.

  12. Differential inhibition of oxidized LDL-induced apoptosis in human endothelial cells treated with different flavonoids.

    PubMed

    Jeong, Yu-Jin; Choi, Yean-Jung; Kwon, Hyang-Mi; Kang, Sang-Wook; Park, Hyoung-Sook; Lee, Myungsook; Kang, Young-Hee

    2005-05-01

    High plasma level of cholesterol is a well-known risk factor for atherosclerotic diseases. Oxidized LDL induces cellular and nuclear damage that leads to apoptotic cell death. We tested the hypothesis that flavonoids may function as antioxidants with regard to LDL incubated with 5 microm-Cu(2+) alone or in combination with human umbilical vein endothelial cells (HUVEC). Cytotoxicity and formation of thiobarbituric acid-reactive substances induced by Cu(2+)-oxidized LDL were examined in the presence of various subtypes of flavonoid. Flavanols, flavonols and flavanones at a non-toxic dose of 50 microm markedly inhibited LDL oxidation by inhibiting the formation of peroxidative products. In contrast, the flavones luteolin and apigenin had no such effect, with >30 % of cells killed after exposure to 0.1 mg LDL/ml. Protective flavonoids, especially (-)-epigallocatechin gallate, quercetin, rutin and hesperetin, inhibited HUVEC nuclear condensation and fragmentation induced by Cu(2+)-oxidized LDL. In addition, immunochemical staining and Western blot analysis revealed that anti-apoptotic Bcl-2 expression was enhanced following treatment with these protective flavonoids. However, Bax expression and caspase-3 cleavage stimulated by 18 h incubation with oxidized LDL were reduced following treatment with these protective flavonoids. The down-regulation of Bcl-2 and up-regulation of caspase-3 activation were reversed by the cytoprotective flavonoids, (-)-epigallocatechin gallate, quercetin and hesperetin, at >/=10 microm. These results suggest that flavonoids may differentially prevent Cu(2+)-oxidized LDL-induced apoptosis and promote cell survival as potent antioxidants. Survival potentials of certain flavonoids against cytotoxic oxidized LDL appeared to stem from their disparate chemical structure. Furthermore, dietary flavonoids may have therapeutic potential for protecting the endothelium from oxidative stress and oxidized LDL-triggered atherogenesis.

  13. Diphenyl diselenide, a simple glutathione peroxidase mimetic, inhibits human LDL oxidation in vitro.

    PubMed

    de Bem, Andreza Fabro; Farina, Marcelo; Portella, Rafael de Lima; Nogueira, Cristina Wayne; Dinis, Teresa C P; Laranjinha, João A N; Almeida, Leonor M; Rocha, João Batista Teixeira

    2008-11-01

    Oxidative modification of low-density lipoprotein (LDL) represents an important factor in atherogenesis. In the present study, we have investigated the antioxidant capability of diphenyl diselenide (PhSe)(2), a simple organoseleno compound, against copper (Cu2+) and peroxyl radical-induced human LDL oxidation in vitro. In initial studies using human serum, (PhSe)(2) caused a dose-dependent inhibition of Cu(2+)-induced lipid peroxidation, which was correlated to thiol consumption. (PhSe)(2) increased lipid peroxidation lag phase and decreased lipid peroxidation rate in isolated human LDL, evaluated by measuring both conjugated diene (CD) and thiobarbituric acid reactive substances (TBARS) levels. Consistent with these observations, (PhSe)(2) showed a marked inhibitory effect on 2,2-azobis(2-amidinopropane dihydrochloride) (AAPH)-induced oxidation of LDL or parinaric acid (PnA) incorporated into LDL. (PhSe)(2) also displayed a dose-dependent protective effect against Cu(2+)-induced lipid peroxidation in rat aortic slices. Interestingly, besides the antioxidant effects of (PhSe)(2) toward the lipid moieties of LDL, which was related to its thiol-peroxidase activity, protein moieties from human isolated LDL were also protected against Cu(2+)-induced oxidation. The results presented herein are the first to show that (i) (PhSe)(2) inhibits lipid peroxidation in human isolated LDL in vitro, (ii) this phenomenon is related to its thiol-peroxidase activity, and (iii) this chalcogen also prevents the oxidation of protein moieties of human LDL. Taken together, such data render (PhSe)(2) a promising molecule for pharmacological studies with respect to the atherogenic process.

  14. MiR-590-5p Inhibits Oxidized- LDL Induced Angiogenesis by Targeting LOX-1

    PubMed Central

    Dai, Yao; Zhang, Zhigao; Cao, Yongxiang; Mehta, Jawahar L.; Li, Jun

    2016-01-01

    Oxidized low-density lipoprotein (ox-LDL) is, at least in part, responsible for angiogenesis in atherosclerotic regions. This effect of ox-LDL has been shown to be mediated through a specific receptor LOX-1. Here we describe the effect of miR-590-5p on ox-LDL-mediated angiogenesis in in vitro and in vivo settings. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-590-5p mimic or inhibitor followed by treatment with ox-LDL. In other experiments, Marigel plugs were inserted in the mice subcutaneous space. Both in vitro and in vivo studies showed that miR-590-5p mimic (100 nM) inhibited the ox-LDL-mediated angiogenesis (capillary tube formation, cell proliferation and migration as well as pro-angiogenic signals- ROS, MAPKs, pro-inflammatory cytokines and adhesion-related proteins). Of note, miR-590-5p inhibitor (200 nM) had the opposite effects. The inhibitory effect of miR-590-5p on angiogenesis was mediated by inhibition of LOX-1 at translational level. The inhibition of LOX-1 by miR-590-5p was confirmed by luciferase assay. In conclusion, we show that MiR-590-5p inhibits angiogenesis by targeting LOX-1 and suppressing redox-sensitive signals. PMID:26932825

  15. MiR-590-5p Inhibits Oxidized- LDL Induced Angiogenesis by Targeting LOX-1.

    PubMed

    Dai, Yao; Zhang, Zhigao; Cao, Yongxiang; Mehta, Jawahar L; Li, Jun

    2016-03-02

    Oxidized low-density lipoprotein (ox-LDL) is, at least in part, responsible for angiogenesis in atherosclerotic regions. This effect of ox-LDL has been shown to be mediated through a specific receptor LOX-1. Here we describe the effect of miR-590-5p on ox-LDL-mediated angiogenesis in in vitro and in vivo settings. Human umbilical vein endothelial cells (HUVECs) were transfected with miR-590-5p mimic or inhibitor followed by treatment with ox-LDL. In other experiments, Marigel plugs were inserted in the mice subcutaneous space. Both in vitro and in vivo studies showed that miR-590-5p mimic (100 nM) inhibited the ox-LDL-mediated angiogenesis (capillary tube formation, cell proliferation and migration as well as pro-angiogenic signals- ROS, MAPKs, pro-inflammatory cytokines and adhesion-related proteins). Of note, miR-590-5p inhibitor (200 nM) had the opposite effects. The inhibitory effect of miR-590-5p on angiogenesis was mediated by inhibition of LOX-1 at translational level. The inhibition of LOX-1 by miR-590-5p was confirmed by luciferase assay. In conclusion, we show that MiR-590-5p inhibits angiogenesis by targeting LOX-1 and suppressing redox-sensitive signals.

  16. Increased uptake of oxidized LDL by macrophages from type 2 diabetics is inhibited by polyamines.

    PubMed

    Balderas, Francisco L; Quezada-Larios, Marina; García Latorre, Ethel Awilda; Méndez, José D

    2016-02-01

    The aim of this study was to evaluate the effect of polyamines putrescine, spermidine and spermine on human LDL oxidation and to assess the ability of macrophages derived from type 2 diabetic patients to uptake oxLDL. Polyamine effect was compared with α-tocopherol. Four healthy subjects and eight type 2 diabetic patients were included in this study. To characterize type 2 diabetic patients and non-diabetic subjects, laboratory test were carried out. Glucose, glycated haemoglobin (HbA1C), triglycerides, low (LDL) and high density lipoproteins (HDL) and serum lipid peroxidation were measured in blood. The study was performed in three stages. For each stage, ten experimental conditions comparing the effect of polyamines with α-tocopherol (10μM solutions) on LDL oxidation and the uptake of oxLDL by macrophages were analyzed. MDA concentration was found to be significantly higher in type 2 diabetic patients compared to healthy subjects (5.6±0.58 vs. 2.66±0.31μM MDA, respectively, (P<0.05)). Percent of macrophages containing oxLDL was determined by means of red oil staining. The uptake of oxLDL by macrophages derived from diabetic patients was clear. The uptake of oxLDL was inhibited when the oxidation was prevented by polyamines or α-tocopherol. Spermine showed high antioxidant capacity (96.67±1.53% vs. 25.67±2.30%) compared to α-tocopherol (96.67±1.53% vs. 47.00±7.20%) at the concentration tested. In conclusion, polyamines especially spermine, has a potent antioxidant effect compared to α-tocopherol on human LDL oxidation, followed by spermidine and putrescine. The results have clinical relevance in the diabetic complications and add knowledge on the role of polyamines as natural antioxidants. This research is not a clinical evaluation rather a functional analysis utilizing clinical samples.

  17. GLP-1 agonists inhibit ox-LDL uptake in macrophages by activating protein kinase A.

    PubMed

    Dai, Yao; Dai, Dongsheng; Wang, Xianwei; Ding, Zufeng; Li, Chunlin; Mehta, Jawahar L

    2014-07-01

    Oxidized low-density lipoprotein (ox-LDL) uptake by monocytes/macrophages plays a pivotal role in atherogenesis. This study was designed to examine the effect of glucagon-like peptide-1 (GLP-1) agonists on ox-LDL uptake in macrophages. Human primary monocytes/macrophages were incubated with native GLP-1 (nGLP-1) or GLP-1 agonist liraglutide to evaluate their effect on ox-LDL uptake and the expression of scavenger receptors (SRs), such as SR-A, CD36, and lectin-like ox-LDL SR-1, in this process. Our study showed a decrease in ox-LDL uptake and CD36 expression in macrophages treated with nGLP-1 or liraglutide. However, nGLP-1 and liraglutide did not affect the expression of other SRs SR-A and lectin-like ox-LDL SR-1. Simultaneously, there was an increase in the expression of activated protein kinase A (PKA). To examine the role of PKA in the effects of nGLP-1 or liraglutide, we treated macrophages with PK inhibitor (6-22) amide, a PKA inhibitor, followed by treatment with nGLP-1 or liraglutide. Inhibition of PKA activation markedly reversed the effect of nGLP-1 or liraglutide on ox-LDL uptake and enhanced the expression of CD36. Our results suggest that GLP-1 agonism inhibits ox-LDL uptake through PKA/CD36 pathway in macrophages. This study provides a novel insight in the mechanism of foam cell formation and the role by GLP-1 agonists therein.

  18. A review of PCSK9 inhibition and its effects beyond LDL receptors.

    PubMed

    Dixon, Dave L; Trankle, Cory; Buckley, Leo; Parod, Eric; Carbone, Salvatore; Van Tassell, Benjamin W; Abbate, Antonio

    2016-01-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an integral role in the degradation of low-density lipoprotein receptors (LDL-R), making it an intriguing target for emerging pharmacotherapy. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved and are available in the United States and European Union. However, much of the PCSK9 story remains to be told. The pipeline for additional pharmacotherapy options is rich with several compounds under development, using alternative strategies for inhibiting PCSK9. Perhaps, more intriguing is the interaction between PCSK9 and non-LDL-R targets, including mediators of inflammation and immunological processes, which remain under intense investigation. This review will discuss the currently available PCSK9 inhibitors, the development of novel approaches to PCSK9 modulation, and the potential non-LDL-R-mediated effects of PCSK9 inhibition.

  19. Nifedipine inhibits ox-LDL-induced lipid accumulation in human blood-derived macrophages.

    PubMed

    Zhang, Qian; Sha Ma, A Zhi; Wang, Chan; Tang, Wei-Qing; Song, Zhi-Yuan

    2015-02-13

    Studies have shown that nifedipine, an anti-hypertensive drug, protects against atherosclerotic progression, but the underlying mechanisms remain elusive. Oxidized low-density lipoprotein (ox-LDL) is critically implicated in macrophage lipid deposition seen in atherosclerosis. In this study, we examined the effects of nifedipine on some ox-LDL-associated changes in human blood-derived macrophages. We isolated monocytes from normal human blood and differentiated them into macrophages. We then treated these human macrophages with ox-LDL and/or nifedipine, and examined lipid accumulation and expression levels of two scavenge receptors CD36 and SR-A as well as a protein kinase PKC-θ. Nifedipine treatment substantially reduced lipid accumulation and the expression of CD36, SR-A, and protein kinase C (PKC)-θ in human macrophages treated with ox-LDL. Silencing of PKC-θ using siRNA also reduced the expression of CD36 and SR-A in these cells. Our results thus suggest that nifedipine may inhibit atherosclerosis by reducing ox-LDL-induced lipid deposition through suppression of the CD36/SR-A-mediated uptake of ox-LDL by macrophages via a PKC-θ-dependent mechanism. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Inhibition of human LDL oxidation by the neuroprotective drug l-deprenyl.

    PubMed

    Thomas, Tom; Bhavnani, Bhagu R; Thomas, Prem

    2002-03-01

    L-deprenyl (Selegiline) used in the treatment of Parkinson's and Alzheimer's disease also enhances longevity. Oxidized low density lipoprotein promotes atherosclerosis and is toxic to both vascular and neural tissue. The reported association between vascular dysfunction and neurodegenerative diseases prompted us to investigate the effect of l-deprenyl, a MAO-B inhibitor, on low density lipoprotein (LDL) oxidation. LDL was isolated from freshly collected blood and the kinetics of copper induced oxidation of LDL was monitored continuously by spectrophotometry. Oral administration (10 mg) or in vitro (2.8 to 84 microM) addition of l-deprenyl inhibited oxidation of LDL isolated from healthy men and post-menopausal women. This is the first report demonstrating that the antioxidant action of l-deprenyl may be antiatherogenic and cardioprotective. Such an action could contribute to reported extension of life span associated with long-term administration of the drug. In conjunction with inhibition of LDL oxidation, l-deprenyl is unique in that it demonstrates protective effects on both vascular and neuronal tissue. Prophylactic use of low doses of l-deprenyl may accord protection against vascular and neurodegenerative diseases associated with aging.

  1. Anti-atherosclerotic potential of gossypetin via inhibiting LDL oxidation and foam cell formation

    SciTech Connect

    Chen, Jing-Hsien; Tsai, Chia-Wen; Wang, Chi-Ping; Lin, Hui-Hsuan

    2013-10-15

    Gossypetin, a flavone originally isolated from Hibiscus species, has been shown to possess antioxidant, antimicrobial, and antimutagenic activities. Here, we investigated the mechanism(s) underlying the anti-atherosclerotic potential of gossypetin. 1,1-Diphenyl-2-picrylhydrazyl (DPPH) scavenging activity assay showed that the addition of > 50 μM of gossypetin could scavenge over 50% of DPPH radicals. The inhibitory effects of gossypetin on the lipid and protein oxidation of LDL were defined by thiobarbituric acid reactive substance (TBARS) assay, the relative electrophoretic mobility (REM) of oxidized LDL (ox-LDL), and fragmentation of apoB in the Cu{sup 2+}-induced oxidation of LDL. Gossypetin showed potential in reducing ox-LDL-induced foam cell formation and intracellular lipid accumulation, and uptake ability of macrophages under non-cytotoxic concentrations. Molecular data showed that these influences of gossypetin might be mediated via peroxisome proliferator-activated receptor α (PPARα)/liver-X receptor α (LXRα)/ATP-binding cassette transporter A1 (ABCA1) and PPARγ/scavenger receptor CD36 pathways, as demonstrated by the transfection of PPARα siRNA or PPARγ expression vector. Our data implied that gossypetin regulated the PPAR signals, which in turn led to stimulation of cholesterol removal from macrophages and delay atherosclerosis. These results suggested that gossypetin potentially could be developed as an anti-atherosclerotic agent. - Highlights: • The anti-atherosclerotic effect of gossypetin in vitro was examined. • Gossypetin inhibited LDL oxidation. • Gossypetin showed potential in reducing on the formation of foam cells. • Gossypetin functions against ox-LDL through PPARa activation and PPARγ depression.

  2. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

    PubMed

    Ishikawa, K; Navab, M; Leitinger, N; Fogelman, A M; Lusis, A J

    1997-09-01

    Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-1 (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-1 induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-1 induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin.

  3. Misfolding of apoprotein B-100, LDL aggregation and 17-β -estradiol in atherogenesis.

    PubMed

    Brunelli, R; De Spirito, M; Mei, G; Papi, M; Perrone, G; Stefanutti, C; Parasassi, T

    2014-01-01

    The long quest for a missing mechanistic rationale accounting for the correlation between plasma cholesterol levels and cardiovascular disease (CVD) has been focused on various possible modifications of low density lipoprotein (LDL), turning this physiological cholesterol carrier into a damaging agent able to trigger atherogenesis and later the onset of the disease. In addition to the debated oxidized LDL (oxLDL), a modified LDL with a misfolded apoprotein B-100, called electronegative LDL(-) for its negative charge due to an increased amount of free fatty acids, is commonly present in plasma. LDL(-) is generated by the action of secretory calcium dependent phospholipase A2. LDL(-) primes LDL aggregation and amyloid formation according to mechanisms very similar to those observed in other misfolding diseases. The LDL particle aggregates recall the structure and size of the subendothelial lipid droplets described in early atherogenesis and elicit a powerful inflammatory response. The use of 17-β-estradiol (E2) confirmed that the suggested atherogenicity of LDL (-) is mostly dependent on the misfolded character of its apoprotein. E2 binding to the apoprotein of native LDL, through a specific and saturable receptor, inhibits misfolding phenomenon despite an unaffected production of LDL (-) by phospholipase A2, ultimately preventing LDL aggregation. The apoprotein misfolding in LDL(-) emerges as a possible significant trigger mechanism of atherogenesis. Potential implications for the development of novel therapeutic approaches might be hypothesized in perspective. The existing evidence is discussed and reported in this review.

  4. Inhibition of LDL oxidation by flavonoids in relation to their structure and calculated enthalpy.

    PubMed

    Vaya, Jacob; Mahmood, Saeed; Goldblum, Amiram; Aviram, Michael; Volkova, Nina; Shaalan, Amin; Musa, Ramadan; Tamir, Snait

    2003-01-01

    Twenty flavonoid compounds of five different subclasses were selected, and the relationship of their structure to the inhibition of low-density lipoprotein (LDL) oxidation in vitro was investigated. The most effective inhibitors, by either copper ion or 2,2'-azobis (2-amidino-propane) dihydrochloride (AAPH) induction, were flavonols and/or flavonoids with two adjacent hydroxyl groups at ring B. In the presence of the later catechol group, the contribution of the double bond and the carbonyl group at ring C was negligible. Isoflavonoids were more effective inhibitors than other flavonoid subclasses with similar structure. Substituting ring B with hydroxyl group(s) at 2' position resulted in a significantly higher inhibitory effect than by substituting ring A or ring B at other positions. The type of LDL inducer had no effect in flavonoids with catechol structure. Calculated heat of formation data (deltadeltaH(f)) revealed that the donation of a hydrogen atom from position 3 was the most likely result, followed by that of a hydroxyl from ring B. Position 3 was favored only in the presence of conjugated double bonds between ring A to ring B. This study makes it possible to assign the contribution of different functional groups among the flavonoid subclasses to in vitro inhibition of LDL oxidation.

  5. Generation in Human Plasma of Misfolded, Aggregation-Prone Electronegative Low Density Lipoprotein

    PubMed Central

    Greco, Giulia; Balogh, Gabor; Brunelli, Roberto; Costa, Graziella; De Spirito, Marco; Lenzi, Laura; Mei, Giampiero; Ursini, Fulvio; Parasassi, Tiziana

    2009-01-01

    Abstract Human plasma contains small amounts of a low density lipoprotein in which apoprotein is misfolded. Originally identified and isolated by means of anion-exchange chromatography, this component was subsequently described as electronegative low density lipoprotein (LDL)(−), with increased concentrations associated with elevated cardiovascular disease risk. It has been recognized recently as the trigger of LDL amyloidogenesis, which produces aggregates similar to subendothelial droplets observed in vivo in early atherogenesis. Although LDL(−) has been produced in vitro through various manipulations, the mechanisms involved in its generation in vivo remain obscure. By using a more physiological model, we demonstrate spontaneous, sustained and noticeable production of LDL(−) during incubation of unprocessed human plasma at 37°C. In addition to a higher fraction of amyloidogenic LDL(−), LDL purified from incubated plasma contains an increased level of lysophospholipids and free fatty acids; analysis of LDL lipids packing shows their loosening. As a result, during plasma incubation, lipid destabilization and protein misfolding take place, and aggregation-prone particles are generated. All these phenomena can be prevented by inhibiting calcium-dependent secretory phospholipases A2. Our plasma incubation model, without removal of reaction products, effectively shows a lipid-protein interplay in LDL, where lipid destabilization after lipolysis threatens the apoprotein's structure, which misfolds and becomes aggregation-prone. PMID:19619478

  6. Vascular incorporation of alpha-tocopherol prevents endothelial dysfunction due to oxidized LDL by inhibiting protein kinase C stimulation.

    PubMed Central

    Keaney, J F; Guo, Y; Cunningham, D; Shwaery, G T; Xu, A; Vita, J A

    1996-01-01

    Excess vascular oxidative stress has been linked to impaired endothelium-dependent arterial relaxation in hypercholesterolemia. alpha-Tocopherol (AT) preserves endothelial function in hypercholesterolemia although the mechanism(s) for this protective effect is (are) not known. We examined the tissue-specific effects of AT on oxidized LDL (ox-LDL)-mediated endothelial dysfunction in male New Zealand White rabbits. Animals consumed chow deficient in (< 10 IU/kg) or supplemented with (1,000 IU/kg) AT for 28 d. Exposure of thoracic aortae from AT-deficient animals to ox-LDL (0-500 microg/ml) for 4 h produced dose-dependent inhibition of acetylcholine-mediated relaxation (P < 0.05) while vessels derived from animals consuming AT were resistant to ox-LDL-mediated endothelial dysfunction. Animals consuming AT demonstrated a 100-fold increase in vascular AT content and this was strongly correlated with vessel resistance to endothelial dysfunction from ox-LDL (R = 0.67; P = 0.0014). These results were not explained by an effect of AT on ox-LDL-mediated cytotoxicity by LDH assay or scanning electron microscopy. Vascular incorporation of AT did produce resistance to endothelial dysfunction from protein kinase C stimulation, an event that has been implicated in the vascular response to ox-LDL. Human aortic endothelial cells loaded with AT also demonstrated resistance to protein kinase C stimulation by both phorbol ester and ox-LDL. Thus, these data indicate that enrichment of vascular tissue with AT protects the vascular endothelium from ox-LDL-mediated dysfunction, at least in part, through the inhibition of protein kinase C stimulation. These findings suggest one potential mechanism for the observed beneficial effect of AT in preventing the clinical expression of coronary artery disease that is distinct from the antioxidant protection of LDL. PMID:8755649

  7. Inhibition of LDL oxidation by a new estradiol receptor modulator compound LY-139478, comparative effect with other steroids.

    PubMed

    Rattan, A K; Arad, Y

    1998-02-01

    Oxidation of low-density lipoprotein (LDL) is postulated to be essential for the development of atherosclerosis. LY-139478 is a new non-steroidal potent estrogen analog, but its effects on in vitro LDL oxidation have not been completely elucidated. We investigated the ability of LY-139478 to inhibit in vitro copper sulfate-mediated LDL oxidation using several methods, including conjugated diene (CD) accumulation, relative electrophoretic mobility on agarose gel, thiobarbituric acid-reactive substances (TBARS) assay, and superoxide anions scavenging activity. The antioxidative potential of LY-139478 was compared to testosterone (T), 17-alpha-estradiol (17alphaE), 17-beta-estradiol (17betaE), dehydroepiandrosterone (D), and dehydroepiandrosterone-3-sulfate (DS). LY-139478 was superior to 17alphaE and 17betaE in prolonging the lag phase and decreasing the slope and peak concentration of the conjugated diene accumulation, decreasing the rate of migration of LDL on agarose gel electrophoresis, and inhibiting the production of melonyldialdehyde (MDA) in the TBARS assay. T, D and DS were ineffective in all three assays. It was previously shown that when native LDL is oxidized by previously oxidized LDL (secondary oxidation) the lag phase is lost (Schnitzer et al. Free Rad Res 1995;23:137). LY-139478 was at least 15-fold more effective than 17alphaE, and 17betaE in slowing the propagation phase and reducing CD accumulation in this secondary oxidation, with 50% inhibition at 10 microM and 98% inhibition at 100 microM. However, none restored the lag phase. T, D and DS were ineffective. Superoxide anion generation was inhibited only by DS at high doses (500 microM). These results demonstrate that LY-139478 is an effective inhibitor of LDL oxidation and is superior to natural steroidal hormones, including 17betaE, in protecting against primary and secondary LDL oxidation.

  8. Electronegativity Equalization with Pauling Units.

    ERIC Educational Resources Information Center

    Bratsch, Steven G.

    1984-01-01

    Discusses electronegativity equalization using Pauling units. Although Pauling has qualitatively defined electronegativity as the power of an atom in a molecule to attract electrons to itself, Pauling electronegativities are treated in this paper as prebonded, isolated-atom quantities. (JN)

  9. Nitric oxide inhibits prooxidant actions of uric acid during copper-mediated LDL oxidation.

    PubMed

    Sanguinetti, Silvia M; Batthyány, Carlos; Trostchansky, Andrés; Botti, Horacio; López, Graciela I; Wikinski, Regina L W; Rubbo, Homero; Schreier, Laura E

    2004-03-15

    Interactions between uric acid and physiologically relevant fluxes of nitric oxide ((?)NO) during copper-mediated low-density lipoprotein (LDL) oxidation were evaluated. In the absence of (?)NO, a dual pro- and antioxidant action of uric acid was evident: low concentrations of uric acid enhanced lipid oxidation and alpha-tocopherol consumption, while its protective role was observed at higher concentrations. The prooxidant effects of uric acid were mostly related to its copper-reducing ability to form Cu(+), an initiator of lipid oxidation processes. While the prooxidant action of uric acid was completely inhibited by (?)NO, the antioxidant action of (?)NO was slightly counterbalanced by uric acid. Enhancement of alpha-tocopherol consumption by uric acid was inhibited in the presence of (?)NO while additive antioxidant effects between (?)NO and uric acid were observed in conditions where uric acid spared alpha-tocopherol. Altogether, these results suggest that in the artery wall, the (?)NO/uric acid pair may exert antioxidant actions on LDL, even if increased amounts of redox active copper were available at conditions favoring prooxidant activities of uric acid.

  10. The effect of electronegativity and angiotensin-converting enzyme inhibition on the kinin-forming capacity of polyacrylonitrile dialysis membranes

    PubMed Central

    Désormeaux, Anik; Moreau, Marie Eve; Lepage, Yves; Chanard, Jacques; Adam, Albert

    2014-01-01

    The combination of negatively-charged membranes and angiotensin I-converting enzyme inhibitors (ACEi) evokes hypersensitivity reactions (HSR) during hemodialysis and bradykinin (BK)-related peptides have been hypothesized as being responsible for these complications. In this study, we tested the effects of neutralizing the membrane electronegativity (zeta potential) of polyacrylonitrile AN69 membranes by coating a polyethyleneimine layer (AN69-ST membranes) over the generation of kinins induced by blood contact with synthetic membranes. We used minidialyzers with AN69 or AN69-ST membranes in an ex vivo model of plasma and we showed that plasma dialysis with AN69 membranes led to significant BK and des-Arg9-BK release, which was potentiated by ACEi. This kinin formation was dramatically decreased by AN69-ST membranes, even in the presence of an ACEi, and kinin recovery in the dialysates was also significantly lower with these membranes. High molecular weight kininogen and factor XII detection by immunoblotting of the protein layer coating both membranes corroborated the results: binding of these proteins and contact system activation on AN69-ST membranes were reduced. This ex vivo experimental model applied to the plasma, dialysate and dialysis membrane could be used for the characterization of the kinin-forming capacity of any biomaterial potentially used in vivo in combination with drugs which modulate the pharmacological activity of kinins. PMID:18078988

  11. Activation of AMP-activated protein kinase inhibits oxidized LDL-triggered endoplasmic reticulum stress in vivo.

    PubMed

    Dong, Yunzhou; Zhang, Miao; Wang, Shuangxi; Liang, Bin; Zhao, Zhengxing; Liu, Chao; Wu, Mingyuan; Choi, Hyoung Chul; Lyons, Timothy J; Zou, Ming-Hui

    2010-06-01

    The oxidation of LDLs is considered a key step in the development of atherosclerosis. How LDL oxidation contributes to atherosclerosis remains poorly defined. Here we report that oxidized and glycated LDL (HOG-LDL) causes aberrant endoplasmic reticulum (ER) stress and that the AMP-activated protein kinase (AMPK) suppressed HOG-LDL-triggered ER stress in vivo. ER stress markers, sarcoplasmic/endoplasmic reticulum Ca(2+) ATPase (SERCA) activity and oxidation, and AMPK activity were monitored in cultured bovine aortic endothelial cells (BAECs) exposed to HOG-LDL or in isolated aortae from mice fed an atherogenic diet. Exposure of BAECs to clinically relevant concentrations of HOG-LDL induced prolonged ER stress and reduced SERCA activity but increased SERCA oxidation. Chronic administration of Tempol (a potent antioxidant) attenuated both SERCA oxidation and aberrant ER stress in mice fed a high-fat diet in vivo. Likewise, AMPK activation by pharmacological (5'-aminoimidazole-4-carboxymide-1-beta-d-ribofuranoside, metformin, and statin) or genetic means (adenoviral overexpression of constitutively active AMPK mutants) significantly mitigated ER stress and SERCA oxidation and improved the endothelium-dependent relaxation in isolated mouse aortae. Finally, Tempol administration markedly attenuated impaired endothelium-dependent vasorelaxation, SERCA oxidation, ER stress, and atherosclerosis in ApoE(-/-) and ApoE(-/-)/AMPKalpha2(-/-) fed a high-fat diet. We conclude that HOG-LDL, via enhanced SERCA oxidation, causes aberrant ER stress, endothelial dysfunction, and atherosclerosis in vivo, all of which are inhibited by AMPK activation.

  12. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

    PubMed Central

    Pinkosky, Stephen L.; Newton, Roger S.; Day, Emily A.; Ford, Rebecca J.; Lhotak, Sarka; Austin, Richard C.; Birch, Carolyn M.; Smith, Brennan K.; Filippov, Sergey; Groot, Pieter H.E.; Steinberg, Gregory R.; Lalwani, Narendra D.

    2016-01-01

    Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy. PMID:27892461

  13. Electronegative Low-density Lipoprotein Increases Coronary Artery Disease Risk in Uremia Patients on Maintenance Hemodialysis

    PubMed Central

    Chang, Chiz-Tzung; Wang, Guei-Jane; Kuo, Chin-Chi; Hsieh, Ju-Yi; Lee, An-Sean; Chang, Chia-Ming; Wang, Chun-Cheng; Shen, Ming-Yi; Huang, Chiu-Ching; Sawamura, Tatsuya; Yang, Chao-Yuh; Stancel, Nicole; Chen, Chu-Huang

    2016-01-01

    Abstract Electronegative low-density lipoprotein (LDL) is a recognized factor in the pathogenesis of coronary artery disease (CAD) in the general population, but its role in the development of CAD in uremia patients is unknown. L5 is the most electronegative subfraction of LDL isolated from human plasma. In this study, we examined the distribution of L5 (L5%) and its association with CAD risk in uremia patients. The LDL of 39 uremia patients on maintenance hemodialysis and 21 healthy controls was separated into 5 subfractions, L1–L5, with increasing electronegativity. We compared the distribution and composition of plasma L5 between uremia patients and controls, examined the association between plasma L5% and CAD risk in uremia patients, and studied the effects of L5 from uremia patients on endothelial function. Compared to controls, uremia patients had significantly increased L5% (P < 0.001) and L5 that was rich in apolipoprotein C3 and triglycerides. L5% was significantly higher in uremia patients with CAD (n = 10) than in those without CAD (n = 29) (P < 0.05). Independent of other major CAD risk factors, the adjusted odds ratio for CAD was 1.88 per percent increase in plasma L5% (95% CI, 1.01–3.53), with a near-linear dose–response relationship. Compared with controls, uremia patients had decreased flow-mediated vascular dilatation. In ex vivo studies with preconstricted rat thoracic aortic rings, L5 from uremia patients inhibited acetylcholine-induced relaxation. In cultured human endothelial cells, L5 inhibited endothelial nitric oxide synthase activation and induced endothelial dysfunction. Our findings suggest that elevated plasma L5% may induce endothelial dysfunction and play an important role in the increased risk of CAD in uremia patients. PMID:26765403

  14. c-Ski inhibits autophagy of vascular smooth muscle cells induced by oxLDL and PDGF.

    PubMed

    Li, Jun; Zhao, Li; Yang, Ting; Zeng, Yi-Jun; Yang, Kang

    2014-01-01

    Autophagy is increasingly being recognized as a critical determinant of vascular smooth muscle cell (VSMC) biology. Previously, we have demonstrated that c-Ski inhibits VSMC proliferation stimulated by transforming growth factor β (TGF-β), but it is not clear whether c-Ski has the similar protective role against other vascular injury factors and whether regulation of autophagy is involved in its protective effects on VSMC. Accordingly, in this study, rat aortic A10 VSMCs were treated with 40 µg/ml oxidized low-density lipoprotein (oxLDL) or 20 ng/ml platelet-derived growth factor (PDGF), both of which were autophagy inducers and closely related to the abnormal proliferation of VSMCs. Overexpression of c-Ski in A10 cells significantly suppressed the oxLDL- and PDGF- induced autophagy. This action of c-Ski resulted in inhibiting the cell proliferation, the decrease of contractile phenotype marker α-SMA expression while the increase of synthetic phenotype marker osteopontin expression stimulated by oxLDL or PDGF. Inversely, knockdown of c-Ski by RNAi enhanced the stimulatory effects of oxLDL or PDGF on A10 cell growth and phenotype transition. And further investigation found that inhibition of AKT phosphorylation to downregulate proliferating cell nuclear antigen (PCNA) expression, was involved in the regulation of autophagy and associated functions by c-Ski in the oxLDL- and PDGF-stimulated VSMCs. Collectively, c-Ski may play an important role in inhibiting autophagy to protect VSMCs against some harsh stress including oxLDL and PDGF.

  15. Nur77 inhibits oxLDL induced apoptosis of macrophages via the p38 MAPK signaling pathway

    SciTech Connect

    Shao, Qin; Han, Fei; Peng, Shi; He, Ben

    2016-03-18

    The interaction between macrophages and oxLDL plays a crucial role in the initiation and progression of atherosclerosis. As a key initiator in a number of plaque promoting processes, oxLDL induces variable effects such as cell apoptosis or proliferation. Orphan nuclear receptor Nur77 is potently induced in macrophages by diverse stimuli, suggesting that it is of importance in vascular inflammation resulting in atherosclerosis, but whether Nur77 induction is detrimental or protective is unclear. In our study, we explore the role of Nur77 in the regulation of oxLDL-induced macrophage apoptosis and the signaling pathways that are involved. We found that oxLDL induced Nur77 expression in a dose and time dependent fashion, and cell viability was decreased in parallel. To determine whether Nur77 induction contributes to the loss of cell viability or is a protective mechanism, the effect of Nur77 overexpression was examined. Importantly, Nur77 overexpression inhibited the oxLDL-induced decrease of cell viability, inhibited the production of apoptotic bodies and restored DNA synthesis following oxLDL exposure. Furthermore, we found that Nur77 induction is mediated through the p38 MAPK signaling pathway. After pretreatment with SB203580, cell viability was decreased, the expression of CyclinA2 and PCNA was attenuated and the percentage of cell apoptosis was enhanced. Likewise, Nur77 overexpression increased the expression of the cell cycle genes PCNA and p21, and attenuated the increase in caspase-3. On the other hand, knockdown of Nur77 expression by specific siRNA resulted in the increased expression of caspase 3. The results demonstrate that Nur77 is induced by oxLDL via the p38 MAPK signaling pathway, which is involved in the regulation of cell survival. Nur77 enhanced cell survival via suppressing apoptosis, without affecting cell proliferation of activated macrophages, which may be beneficial in patients with atherosclerosis. - Highlights: • oxLDL could induce Nur77

  16. Anacetrapib reduces (V)LDL cholesterol by inhibition of CETP activity and reduction of plasma PCSK9[S

    PubMed Central

    van der Tuin, Sam J. L.; Kühnast, Susan; Berbée, Jimmy F. P.; Verschuren, Lars; Pieterman, Elsbet J.; Havekes, Louis M.; van der Hoorn, José W. A.; Rensen, Patrick C. N.; Jukema, J. Wouter; Princen, Hans M. G.; Willems van Dijk, Ko; Wang, Yanan

    2015-01-01

    Recently, we showed in APOE*3-Leiden cholesteryl ester transfer protein (E3L.CETP) mice that anacetrapib attenuated atherosclerosis development by reducing (V)LDL cholesterol [(V)LDL-C] rather than by raising HDL cholesterol. Here, we investigated the mechanism by which anacetrapib reduces (V)LDL-C and whether this effect was dependent on the inhibition of CETP. E3L.CETP mice were fed a Western-type diet alone or supplemented with anacetrapib (30 mg/kg body weight per day). Microarray analyses of livers revealed downregulation of the cholesterol biosynthesis pathway (P < 0.001) and predicted downregulation of pathways controlled by sterol regulatory element-binding proteins 1 and 2 (z-scores −2.56 and −2.90, respectively; both P < 0.001). These data suggest increased supply of cholesterol to the liver. We found that hepatic proprotein convertase subtilisin/kexin type 9 (Pcsk9) expression was decreased (−28%, P < 0.01), accompanied by decreased plasma PCSK9 levels (−47%, P < 0.001) and increased hepatic LDL receptor (LDLr) content (+64%, P < 0.01). Consistent with this, anacetrapib increased the clearance and hepatic uptake (+25%, P < 0.001) of [14C]cholesteryl oleate-labeled VLDL-mimicking particles. In E3L mice that do not express CETP, anacetrapib still decreased (V)LDL-C and plasma PCSK9 levels, indicating that these effects were independent of CETP inhibition. We conclude that anacetrapib reduces (V)LDL-C by two mechanisms: 1) inhibition of CETP activity, resulting in remodeled VLDL particles that are more susceptible to hepatic uptake; and 2) a CETP-independent reduction of plasma PCSK9 levels that has the potential to increase LDLr-mediated hepatic remnant clearance. PMID:26342106

  17. Syzygium cumini leaf extract inhibits LDL oxidation, but does not protect the liproprotein from glycation.

    PubMed

    Dos Santos, Matheus M; Prestes, Alessandro S; de Macedo, Gabriel T; Ecker, Assis; Barcelos, Rômulo P; Boligon, Aline A; Souza, Diego; de Bem, Andreza F; da Rocha, João B T; Barbosa, Nilda V

    2017-08-26

    Syzygium cumini (L.) Skeels is a plant widely used in folk medicine to treat diabetes mellitus (DM). The tea from its leaves is frequently used by diabetics for lowering hyperglycemia. There is a close relationship between DM and atherosclerosis, a chronic immuno-inflammatory disease, were the early stages encompass oxidative and glycative modifications in the structure of low density lipoprotein (LDL). To investigate the potential protective effects of aqueous-leaf extract from Syzygium cumini (S.cExt) against CuSO4-induced oxidation and methylglyoxal (MG)-induced glycation of human LDL in vitro. LDL oxidative changes were evaluated by measuring conjugated dienes (CD) formation, thiobarbituric acid reactive substances (TBARS) levels, quenching of tryptophan (Trp) fluorescence and structural modifications in LDL particle. In LDL glycated by MG (glyLDL), we determined the levels of fluorescent advanced glycation end products (AGEs) and mobility by agarose gel electrophoresis. S.cExt blocked oxidative events induced by CuSO4 in human LDL, plasma and serum. Fourier transform infrared spectroscopy (FT-IR) revealed that specific regions of apoB100 were oxidized by CuSO4 in human LDL and that S.cExt reduced these oxidations. Unlike, the increased AGEs levels and eletrophoretic mobility observed in LDL MG-glycated were not modified by S.cExt. The findings herein indicate that S.cExt could be tested in atherogenesis models as potential protective agent against LDL oxidation. Copyright © 2017 Elsevier B.V. All rights reserved.

  18. Electronegativity Equalization and Partial Charge

    ERIC Educational Resources Information Center

    Sanderson, R. T.

    1974-01-01

    This article elaborates the relationship between covalent radius, homonuclear bond energy, and electronegativity, and sets the background for bond energy calculation by discussing the nature of heteronuclear covalent bonding on the basis of electronegativity equalization and particle charge. (DT)

  19. Electronegativity Equalization and Partial Charge

    ERIC Educational Resources Information Center

    Sanderson, R. T.

    1974-01-01

    This article elaborates the relationship between covalent radius, homonuclear bond energy, and electronegativity, and sets the background for bond energy calculation by discussing the nature of heteronuclear covalent bonding on the basis of electronegativity equalization and particle charge. (DT)

  20. Atractylenolide I restores HO-1 expression and inhibits Ox-LDL-induced VSMCs proliferation, migration and inflammatory responses in vitro.

    PubMed

    Li, Weifeng; Zhi, Wenbing; Liu, Fang; He, Zehong; Wang, Xiuei; Niu, Xiaofeng

    2017-04-01

    Pathogenesis of atherosclerosis is characterized by the proliferation and migration of vascular smooth muscle cells (VSMCs) and inflammatory lesions. The aim of this study is to elucidate the effect of atractylenolide I (AO-I) on smooth muscle cell inflammation, proliferation and migration induced by oxidized modified low density lipoprotein (Ox-LDL). Here, We found that atractylenolide I inhibited Ox-LDL-induced VSMCs proliferation and migration in a dose-dependent manner, and decreased the production of inflammatory cytokines and the expression of monocyte chemoattractant protein-1 (MCP-1) in VSMCs. The study also identified that AO-I prominently inhibited p38-MAPK and NF-κB activation. More importantly, the specific heme oxygenase-1 (HO-1) inhibitor zinc protoporphyrin (ZnPP) IX partially abolished the beneficial effects of atractylenolide I on Ox-LDL-induced VSMCs. Furthermore, atractylenolide I blocked the foam cell formation in macrophages induced by Ox-LDL. In summary, inhibitory roles of AO-I in VSMCs proliferation and migration, lipid peroxidation and subsequent inflammatory responses might contribute to the anti-atherosclerotic property of AO-I. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. MicroRNA-221/222 regulate ox-LDL-induced endothelial apoptosis via Ets-1/p21 inhibition.

    PubMed

    Qin, Bing; Cao, Yuze; Yang, Huan; Xiao, Bo; Lu, Zhengqi

    2015-07-01

    Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play an essential role in atherosclerosis. MicroRNAs (miRNAs) are a class of short non-coding RNAs, acting as posttranscriptional regulators of protein-coding genes involved in vascular cell biology. MiRNA-221 and miRNA-222 (miR-221/222) are known to be involved in the regulation of endothelial inflammation and angiogenesis. However, the function of miR-221/222 in ox-LDL-induced ECs apoptosis and atherosclerosis is still unknown. Here, we showed that miR-221/222 expression was markedly down-regulated in ox-LDL-induced apoptotic human umbilical cord vein endothelial cells. MiR-221/222 inhibition enhanced apoptosis in ECs, whereas over-expression of miR-221/222 could partly alleviate apoptotic cell death mediated by ox-LDL through suppression of Ets-1 and its downstream target p21. These findings suggest that manipulation of the miR-221/222-Ets-1-p21 pathway may offer a novel strategy for treatment of endothelial apoptosis and atherosclerosis.

  2. Modeling electronegative plasma discharge

    SciTech Connect

    Lichtenberg, A.J.; Lieberman, M.A.

    1995-12-31

    Macroscopic analytic models for a three-component electronegative gas discharge are developed. Assuming the negative ions to be in Boltzmann equilibrium, a positive ion ambipolar diffusion equation is derived. The discharge consists of an electronegative core and electropositive edges. The electron density in the core is nearly uniform, allowing a parabolic approximation to the plasma profile to be employed. The resulting equilibrium equations are solved analytically and matched to a constant mobility transport model of an electropositive edge plasma. The solutions are compared to a simulation of a parallel-plane r.f. driven oxygen plasma for p = 50 mTorr and n{sub eo}= 2.4 x 10{sup 15} m{sup -3}. The ratio {alpha}{sub o} of central negative ion density to electron density, and the electron temperature T{sub e}, found in the simulation, are in reasonable agreement with the values calculated from the model. The model is extended to: (1) low pressures, where a variable mobility model is used in the electropositive edge region; and (2) high {alpha}{sub o} in which the edge region disappears. The inclusion of a second positive ion species, which can be very important in describing electronegative discharges used for materials processing, is a possible extension of the model.

  3. EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells.

    PubMed

    Jiang, Jun-xia; Zhang, Shui-juan; Liu, Ya-nan; Lin, Xi-xi; Sun, Yan-hong; Shen, Hui-juan; Yan, Xiao-feng; Xie, Qiang-min

    2014-03-15

    Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1μM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100μg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted.

  4. NDRG2 induced by oxidized LDL in macrophages antagonizes growth factor productions via selectively inhibiting ERK activation.

    PubMed

    Liu, Shumei; Yang, Pengyuan; Kang, Hui; Lu, Ling; Zhang, Yuefan; Pan, Jingwei; Rui, Yao-Cheng

    2010-02-01

    During atherogenesis, macrophage foam cells produce prodigious growth factors, cytokines, and chemokines, which play the central roles in inflammatory process in atherosclerotic plaque formation. In the present study, we identified a new protein marker, N-Myc downstream-regulated protein 2 (NDRG2), which is significantly up-regulated in oxidized low density lipoprotein (oxLDL) treated macrophages and in human atherosclerotic plaques. Over-expression and siRNA knockdown studies showed that NDRG2 is a negative regulator of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) productions in macrophages. Furthermore, we investigated the effects of NDRG2 on MAPK signal activation. Our results showed ERK1/2 activation, but not P38 or JNK1/2 activation, is responsible for regulation of NDRG2 on VEGF and PDGF productions. Consistent with the PDGF levels, the vascular smooth muscle cell (VSMC) proliferation was also regulated by the conditional medium of the oxLDL treated macrophages with NDRG2 knockdown or over-expression. Neutralizing anti-PDGF antibody can significantly inhibit the enhanced VSMC proliferation by macrophage medium with NDRG2 knockdown. Our present results demonstrate that NDRG2 participates in oxLDL-induced macrophage activation and modulates ERK1/2-dependent PDGF and VEGF production, which has potential application in atherogenesis. 2009 Elsevier B.V. All rights reserved.

  5. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway.

    PubMed

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-07-29

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation.

  6. High-density lipoprotein inhibits ox-LDL-induced adipokine secretion by upregulating SR-BI expression and suppressing ER Stress pathway

    PubMed Central

    Song, Guohua; Wu, Xia; Zhang, Pu; Yu, Yang; Yang, Mingfeng; Jiao, Peng; Wang, Ni; Song, Haiming; Wu, You; Zhang, Xiangjian; Liu, Huaxia; Qin, Shucun

    2016-01-01

    Endoplasmic reticulum stress (ERS) in adipocytes can modulate adipokines secretion. The aim of this study was to explore the protective effect of high-density lipoprotein (HDL) on oxidized low-density lipoprotein (ox-LDL)-induced ERS-C/EBP homologous protein (CHOP) pathway-mediated adipokine secretion. Our results showed that serum adipokines, including visfatin, resistin and TNF-α, correlated inversely with serum HDL cholesterol level in patients with abdominal obesity. In vitro, like ERS inhibitor 4-phenylbutyric acid (PBA), HDL inhibited ox-LDL- or tunicamycin (TM, an ERS inducer)-induced increase in visfatin and resistin secretion. Moreover, HDL inhibited ox-LDL-induced free cholesterol (FC) accumulation in whole cell lysate and in the endoplasmic reticulum. Additionally, like PBA, HDL inhibited ox-LDL- or TM-induced activation of ERS response as assessed by the decreased phosphorylation of protein kinase-like ER kinase and eukaryotic translation initiation factor 2α and reduced nuclear translocation of activating transcription factor 6 as well as the downregulation of Bip and CHOP. Furthermore, HDL increased scavenger receptor class B type I (SR-BI) expression and SR-BI siRNA treatment abolished the inhibitory effects of HDL on ox-LDL-induced FC accumulation and CHOP upregulation. These data indicate that HDL may suppress ox-LDL-induced FC accumulation in adipocytes through upregulation of SR-BI, subsequently preventing ox-LDL-induced ER stress-CHOP pathway-mediated adipocyte inflammation. PMID:27468698

  7. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.

    PubMed

    Cheng, Fei; Twardowski, Laura; Fehr, Sarah; Aner, Christoph; Schaeffeler, Elke; Joos, Thomas; Knorpp, Thomas; Dorweiler, Bernhard; Laufer, Stefan; Schwab, Matthias; Torzewski, Michael

    2017-02-01

    The first ATP-competitive p38α MAPK/MAPK14 inhibitor with excellent in vivo efficacy and selectivity, skepinone-L, is now available. We investigated the impact of selective p38α MAPK/MAPK14 inhibition on enzymatically modified LDL (eLDL) stimulated human monocytes with its implications for atherosclerosis. Among the different p38 MAPK isoforms, p38α/MAPK14 was the predominantly expressed and activated isoform in isolated human peripheral blood monocytes. Moreover, eLDL colocalized with macrophages positive for p38α MAPK/MAPK14 in human carotid endarterectomy specimens. Using the human leukemia cell line THP-1 and/or primary monocyte-derived macrophages, skepinone-L inhibited eLDL-induced activation of the p38 MAPK pathway, inhibited eLDL induced expression of both cluster of differentiation 36 (CD36) and ATP-binding cassette, subfamily A, member 1 (ABCA1), without a net effect on foam cell formation, had a cell- and time-dependent effect on eLDL-triggered apoptosis, and inhibited eLDL-stimulated secretion of IL-8 and MIP-1β/CCL4 (macrophage inflammatory protein-1β/chemokine, CC motif, ligand 4). Inhibition of a key signaling molecule of the p38 MAPK pathway, p38α MAPK/MAPK14, by selective inhibitors like skepinone-L, conclusively facilitates elucidation of the impact of the complex network of p38 MAPK signaling on atherogenesis and might provide a promising therapeutic tool to prevent inflammatory cascades in atherosclerosis.-Cheng, F., Twardowski, L., Fehr, S., Aner, C., Schaeffeler, E., Joos, T., Knorpp, T., Dorweiler, B., Laufer, S., Schwab, M., Torzewski, M. Selective p38α MAP kinase/MAPK14 inhibition in enzymatically modified LDL-stimulated human monocytes: implications for atherosclerosis.

  8. Quercetin Inhibits LPS-Induced Inflammation and ox-LDL-Induced Lipid Deposition.

    PubMed

    Xue, Feng; Nie, Xiaobo; Shi, Jianping; Liu, Qingxue; Wang, Ziwei; Li, Xiting; Zhou, Jinqiu; Su, Jia; Xue, Mingming; Chen, Wei-Dong; Wang, Yan-Dong

    2017-01-01

    Aberrant activation of inflammation and excess accumulation of lipids play crucial role in the occurrence and progression of atherosclerosis (AS). Quercetin (QCT) has been tested effectively to cure AS. It is widely distributed in plant foods and has been proved to have potential antioxidative and anticancer activities. However, the underlying molecular mechanisms of OCT in AS are not completely understood. In the present study, we stimulated murine RAW264.7 cells with lipopolysaccharide (LPS) or oxidized low-density lipoproteins (ox-LDL) to mimic the development of AS. The data show that QCT treatment leads to an obvious decrease of multiple inflammatory cytokines in transcript level, including interleukin (IL)-1α, IL-1β, IL-2, IL-10, macrophage chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) induced by LPS. Moreover, expressions of other factors that contribute to the AS development, such as matrix metalloproteinase-1 (MMP-1) and suppressor of cytokine signaling 3 (SOCS3) induced by LPS are also downregulated by QCT. Furthermore, we found that QCT suppressed LPS-induced the phosphorylation of STAT3. Meanwhile, QCT could ameliorate lipid deposition and overproduction of reactive oxygen species induced by ox-LDL, and block the expression of lectin-like oxidized LDL receptor-1 (LOX-1) in cultured macrophages. Taken together, our data reveal that QCT has obvious anti-inflammatory and antioxidant virtues and could be a therapeutic agent for the prevention and treatment of AS.

  9. Quercetin Inhibits LPS-Induced Inflammation and ox-LDL-Induced Lipid Deposition

    PubMed Central

    Xue, Feng; Nie, Xiaobo; Shi, Jianping; Liu, Qingxue; Wang, Ziwei; Li, Xiting; Zhou, Jinqiu; Su, Jia; Xue, Mingming; Chen, Wei-Dong; Wang, Yan-Dong

    2017-01-01

    Aberrant activation of inflammation and excess accumulation of lipids play crucial role in the occurrence and progression of atherosclerosis (AS). Quercetin (QCT) has been tested effectively to cure AS. It is widely distributed in plant foods and has been proved to have potential antioxidative and anticancer activities. However, the underlying molecular mechanisms of OCT in AS are not completely understood. In the present study, we stimulated murine RAW264.7 cells with lipopolysaccharide (LPS) or oxidized low-density lipoproteins (ox-LDL) to mimic the development of AS. The data show that QCT treatment leads to an obvious decrease of multiple inflammatory cytokines in transcript level, including interleukin (IL)-1α, IL-1β, IL-2, IL-10, macrophage chemoattractant protein-1 (MCP-1), and cyclooxygenase-2 (COX-2) induced by LPS. Moreover, expressions of other factors that contribute to the AS development, such as matrix metalloproteinase-1 (MMP-1) and suppressor of cytokine signaling 3 (SOCS3) induced by LPS are also downregulated by QCT. Furthermore, we found that QCT suppressed LPS-induced the phosphorylation of STAT3. Meanwhile, QCT could ameliorate lipid deposition and overproduction of reactive oxygen species induced by ox-LDL, and block the expression of lectin-like oxidized LDL receptor-1 (LOX-1) in cultured macrophages. Taken together, our data reveal that QCT has obvious anti-inflammatory and antioxidant virtues and could be a therapeutic agent for the prevention and treatment of AS. PMID:28217098

  10. Hyperhalogens and highly electronegative compositions

    DOEpatents

    Jena, Puru; Gantefoer, Gerd

    2016-08-16

    Hyperhalogens, a new class of highly electronegative species, are now invented. A hyperhalogen is a superhalogen-containing composition in which the electron affinity (EA) of the hyperhalogen is even larger than that of the superhalogens they are composed of. Novel production methods are provided in which highly electronegative species are produced by surrounding a central metal atom by superhalogen moieties.

  11. Electronegative Gas Thruster

    NASA Technical Reports Server (NTRS)

    Dankanich, John; Polzin, Kurt; Walker, Mitchell

    2015-01-01

    The project is an international collaboration and academic partnership to mature an innovative electric propulsion thruster concept to Technology Research Level-3 (TRL-3) through direct thrust measurement. The project includes application assessment of the technology ranging from small spacecraft to high power. The Plasma propulsion with Electronegative GASES(PEGASES) basic proof of concept has been matured to TRL-2 by Ane Aanesland of Laboratoire de Physique des Plasma at Ecole Polytechnique. The concept has advantages through eliminating the neutralizer requirement and should yield longer life and lower cost over conventional gridded ion engines. The objective of this research is to validate the proof of concept through the first direct thrust measurements and mature the concept to TRL-3.

  12. Electronegativity, Bond Energy, and Chemical Reactivity.

    ERIC Educational Resources Information Center

    Myers, R. Thomas

    1979-01-01

    Discusses the Pauling electronegativity concept which rationalizes several kinds of chemical reactions of covalent substances. Electronegativity differences applied to some reactions are demonstrated. (SA)

  13. Electronegativity, Bond Energy, and Chemical Reactivity.

    ERIC Educational Resources Information Center

    Myers, R. Thomas

    1979-01-01

    Discusses the Pauling electronegativity concept which rationalizes several kinds of chemical reactions of covalent substances. Electronegativity differences applied to some reactions are demonstrated. (SA)

  14. Connecting Pauling and Mulliken Electronegativities.

    PubMed

    Herrick, David R

    2005-03-01

    A conversion formula between Pauling and Mulliken electronegativities is derived from a new analytic treatment of the classic valence bond model for a single bond A-B in terms of Mulliken-Jaffe "a and b" parameters for the atomic valence states. The new formula works better than the traditional linear and half-power empirical formulas. The results are consistent with an absolute Pauling scale in which both electronegativities approach zero simultaneously.

  15. Oxidized LDL activates blood platelets through CD36/NOX2–mediated inhibition of the cGMP/protein kinase G signaling cascade

    PubMed Central

    Magwenzi, Simbarashe; Woodward, Casey; Wraith, Katie S.; Aburima, Ahmed; Raslan, Zaher; Jones, Huw; McNeil, Catriona; Wheatcroft, Stephen; Yuldasheva, Nadira; Febbriao, Maria; Kearney, Mark

    2015-01-01

    Oxidized low-density lipoprotein (oxLDL) promotes unregulated platelet activation in dyslipidemic disorders. Although oxLDL stimulates activatory signaling, it is unclear how these events drive accelerated thrombosis. Here, we describe a mechanism for oxLDL-mediated platelet hyperactivity that requires generation of reactive oxygen species (ROS). Under arterial flow, oxLDL triggered sustained generation of platelet intracellular ROS, which was blocked by CD36 inhibitors, mimicked by CD36-specific oxidized phospholipids, and ablated in CD36−/− murine platelets. oxLDL-induced ROS generation was blocked by the reduced NAD phosphate oxidase 2 (NOX2) inhibitor, gp91ds-tat, and absent in NOX2−/− mice. The synthesis of ROS by oxLDL/CD36 required Src-family kinases and protein kinase C (PKC)-dependent phosphorylation and activation of NOX2. In functional assays, oxLDL abolished guanosine 3′,5′-cyclic monophosphate (cGMP)-mediated signaling and inhibited platelet aggregation and arrest under flow. This was prevented by either pharmacologic inhibition of NOX2 in human platelets or genetic ablation of NOX2 in murine platelets. Platelets from hyperlipidemic mice were also found to have a diminished sensitivity to cGMP when tested ex vivo, a phenotype that was corrected by infusion of gp91ds-tat into the mice. This study demonstrates that oxLDL and hyperlipidemia stimulate the generation of NOX2-derived ROS through a CD36-PKC pathway and may promote platelet hyperactivity through modulation of cGMP signaling. PMID:25710879

  16. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice

    PubMed Central

    Kritikou, Eva; van Puijvelde, Gijs H. M.; van der Heijden, Thomas; van Santbrink, Peter J.; Swart, Maarten; Schaftenaar, Frank H.; Kröner, Mara J.; Kuiper, Johan; Bot, Ilze

    2016-01-01

    Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6Clow monocytes and CD4+ CD25+ FoxP3+ T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development. PMID:27883026

  17. Inhibition of lysophosphatidic acid receptors 1 and 3 attenuates atherosclerosis development in LDL-receptor deficient mice.

    PubMed

    Kritikou, Eva; van Puijvelde, Gijs H M; van der Heijden, Thomas; van Santbrink, Peter J; Swart, Maarten; Schaftenaar, Frank H; Kröner, Mara J; Kuiper, Johan; Bot, Ilze

    2016-11-24

    Lysophosphatidic acid (LPA) is a natural lysophospholipid present at high concentrations within lipid-rich atherosclerotic plaques. Upon local accumulation in the damaged vessels, LPA can act as a potent activator for various types of immune cells through its specific membrane receptors LPA1/3. LPA elicits chemotactic, pro-inflammatory and apoptotic effects that lead to atherosclerotic plaque progression. In this study we aimed to inhibit LPA signaling by means of LPA1/3 antagonism using the small molecule Ki16425. We show that LPA1/3 inhibition significantly impaired atherosclerosis progression. Treatment with Ki16425 also resulted in reduced CCL2 production and secretion, which led to less monocyte and neutrophil infiltration. Furthermore, we provide evidence that LPA1/3 blockade enhanced the percentage of non-inflammatory, Ly6C(low) monocytes and CD4(+) CD25(+) FoxP3(+) T-regulatory cells. Finally, we demonstrate that LPA1/3 antagonism mildly reduced plasma LDL cholesterol levels. Therefore, pharmacological inhibition of LPA1/3 receptors may prove a promising approach to diminish atherosclerosis development.

  18. LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118

    PubMed Central

    Doeppner, Thorsten R.; Niu, Feng; Li, Qiaochuan; Yang, Yanping; Kuckelkorn, Ulrike; Hagemann, Nina; Li, Wei; Hermann, Dirk M.; Dai, Yun; Zhou, Wen; Jin, Fengyan

    2015-01-01

    Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure. Significantly, the proteasome inhibitor BSc2118 prevented angiogenesis attenuation by LDL through restoring expression of HIFs. Together, these findings argue that HIF-1β might act as a novel cross-link between the HIF and NF-κB pathways in suppression of angiogenesis by LDL, while proteasome inhibitors might promote angiogenesis by reactivating this signaling cascade under hyperlipidemia. PMID:26388611

  19. LDL suppresses angiogenesis through disruption of the HIF pathway via NF-κB inhibition which is reversed by the proteasome inhibitor BSc2118.

    PubMed

    Yao, Gang; Zhang, Qi; Doeppner, Thorsten R; Niu, Feng; Li, Qiaochuan; Yang, Yanping; Kuckelkorn, Ulrike; Hagemann, Nina; Li, Wei; Hermann, Dirk M; Dai, Yun; Zhou, Wen; Jin, Fengyan

    2015-10-06

    Since disturbance of angiogenesis predisposes to ischemic injuries, attempts to promote angiogenesis have been made to improve clinical outcomes of patients with many ischemic disorders. While hypoxia inducible factors (HIFs) stimulate vascular remodeling and angiogenesis, hyperlipidemia impairs angiogenesis in response to various pro-angiogenic factors. However, it remains uncertain how HIFs regulate angiogenesis under hyperlipidemia. Here, we report that exposure to low-density lipoprotein (LDL) suppressed in vitro angiogenesis of human brain microvascular endothelial cells. Whereas LDL exposure diminished expression of HIF-1α and HIF-2α induced by hypoxia, it inhibited DMOG- and TNFα-induced HIF-1α and HIF-2α expression in normoxia. Notably, in both hypoxia and normoxia, LDL markedly reduced expression of HIF-1β, a constitutively stable HIF subunit, an event associated with NF-κB inactivation. Moreover, knockdown of HIF-1β down-regulated HIF-1α and HIF-2α expression, in association with increased HIF-1α hydroxylation and 20S proteasome activity after LDL exposure. Significantly, the proteasome inhibitor BSc2118 prevented angiogenesis attenuation by LDL through restoring expression of HIFs. Together, these findings argue that HIF-1β might act as a novel cross-link between the HIF and NF-κB pathways in suppression of angiogenesis by LDL, while proteasome inhibitors might promote angiogenesis by reactivating this signaling cascade under hyperlipidemia.

  20. L5-LDL from ST-elevation myocardial infarction patients induces IL-1β production via LOX-1 and NLRP3 inflammasome activation in macrophages.

    PubMed

    Yang, Tzu-Ching; Chang, Po-Yuan; Lu, Shao-Chun

    2017-02-01

    L5-LDL, the most electronegative LDL associated with major cardiovascular risks, significantly rises in patients with ST-segment elevation myocardial infarction (STEMI). The inflammatory nature of atherosclerotic vascular diseases has prompted us to investigate whether L5-LDL induces the production of inflammatory cytokines, especially vascular ischemia-related interleukin (IL)-1β, in the pathogenesis of STEMI. Clinical data showed that plasma levels of L5-LDL and IL-1β were higher in the STEMI patients than in the controls (P < 0.05). In THP-1-derived human macrophages, L5-LDL significantly increased the levels of both IL-1β and cleaved caspase-1, indicating the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasomes by L5-LDL. Knockdown of NLRP3 and its adaptor protein apoptosis-associated speck-like protein containing a CARD (ASC) resulted in decreased L5-LDL-induced IL-1β. Furthermore, knock down of the lectin-type oxidized LDL receptor (LOX-1) in THP-1 cells attenuated L5-LDL-induced activation of NF-κB and caspase-1, leading to subsequent inhibition of IL-1β in macrophages. Furthermore, blockade LOX-1 with neutralizing antibody also inhibited L5-LDL-induced IL-1β in human peripheral blood mononuclear cell-derived macrophages. In conclusion, L5-LDL induces IL-1β production in macrophages by activation of NF-κB and caspase-1 through the LOX-1-dependent pathway. This study represents the evidence linking L5-LDL and the inflammatory cytokine IL-1β in STEMI, and identifies L5-LDL as a novel therapeutic target in acute myocardial infarction.

  1. ApoB100-LDL Acts as a Metabolic Signal from Liver to Peripheral Fat Causing Inhibition of Lipolysis in Adipocytes

    PubMed Central

    Skogsberg, Josefin; Dicker, Andrea; Rydén, Mikael; Åström, Gaby; Nilsson, Roland; Bhuiyan, Hasanuzzaman; Vitols, Sigurd; Mairal, Aline; Langin, Dominique; Alberts, Peteris; Walum, Erik; Tegnér, Jesper; Hamsten, Anders; Arner, Peter; Björkegren, Johan

    2008-01-01

    Background Free fatty acids released from adipose tissue affect the synthesis of apolipoprotein B-containing lipoproteins and glucose metabolism in the liver. Whether there also exists a reciprocal metabolic arm affecting energy metabolism in white adipose tissue is unknown. Methods and Findings We investigated the effects of apoB-containing lipoproteins on catecholamine-induced lipolysis in adipocytes from subcutaneous fat cells of obese but otherwise healthy men, fat pads from mice with plasma lipoproteins containing high or intermediate levels of apoB100 or no apoB100, primary cultured adipocytes, and 3T3-L1 cells. In subcutaneous fat cells, the rate of lipolysis was inversely related to plasma apoB levels. In human primary adipocytes, LDL inhibited lipolysis in a concentration-dependent fashion. In contrast, VLDL had no effect. Lipolysis was increased in fat pads from mice lacking plasma apoB100, reduced in apoB100-only mice, and intermediate in wild-type mice. Mice lacking apoB100 also had higher oxygen consumption and lipid oxidation. In 3T3-L1 cells, apoB100-containing lipoproteins inhibited lipolysis in a dose-dependent fashion, but lipoproteins containing apoB48 had no effect. ApoB100-LDL mediated inhibition of lipolysis was abolished in fat pads of mice deficient in the LDL receptor (Ldlr−/−Apob100/100). Conclusions Our results show that the binding of apoB100-LDL to adipocytes via the LDL receptor inhibits intracellular noradrenaline-induced lipolysis in adipocytes. Thus, apoB100-LDL is a novel signaling molecule from the liver to peripheral fat deposits that may be an important link between atherogenic dyslipidemias and facets of the metabolic syndrome. PMID:19020660

  2. LDL-Induced Impairment of Human Vascular Smooth Muscle Cells Repair Function Is Reversed by HMG-CoA Reductase Inhibition

    PubMed Central

    Padró, Teresa; Lugano, Roberta; García-Arguinzonis, Maisa; Badimon, Lina

    2012-01-01

    Growing human atherosclerotic plaques show a progressive loss of vascular smooth muscle cells (VSMC) becoming soft and vulnerable. Lipid loaded-VSMC show impaired vascular repair function and motility due to changes in cytoskeleton proteins involved in cell-migration. Clinical benefits of statins reducing coronary events have been related to repopulation of vulnerable plaques with VSMC. Here, we investigated whether HMG-CoA reductase inhibition with rosuvastatin can reverse the effects induced by atherogenic concentrations of LDL either in the native (nLDL) form or modified by aggregation (agLDL) on human VSMC motility. Using a model of wound repair, we showed that treatment of human coronary VSMC with rosuvastatin significantly prevented (and reversed) the inhibitory effect of nLDL and agLDL in the repair of the cell depleted areas. In addition, rosuvastatin significantly abolished the agLDL-induced dephosphorylation of myosin regulatory light chain as demonstrated by 2DE-electrophoresis and mass spectrometry. Besides, confocal microscopy showed that rosuvastatin enhances actin-cytoskeleton reorganization during lipid-loaded-VSMC attachment and spreading. The effects of rosuvastatin on actin-cytoskeleton dynamics and cell migration were dependent on ROCK-signalling. Furthermore, rosuvastatin caused a significant increase in RhoA-GTP in the cytosol of VSMC. Taken together, our study demonstrated that inhibition of HMG-CoA reductase restores the migratory capacity and repair function of VSMC that is impaired by native and aggregated LDL. This mechanism may contribute to the stabilization of lipid-rich atherosclerotic plaques afforded by statins. PMID:22719992

  3. Cloning and expression of an anti-LDL(-) single-chain variable fragment, and its inhibitory effect on experimental atherosclerosis.

    PubMed

    Kazuma, Soraya M; Cavalcante, Marcela F; Telles, Andréia E R; Maranhão, Andrea Queiroz; Abdalla, Dulcineia S P

    2013-01-01

    The in vivo modified forms of low-density lipoprotein (LDL) are important for the formation of foam cells and as mediators of the immuno-inflammatory process involved in the progression of atherosclerosis. Electronegative LDL, LDL(-), is a LDL subfraction with pro-inflammatory properties that is present in human blood. To investigate possible atheroprotective effects, an anti-LDL(-) single-chain variable fragment (scFv) was expressed in the methylotrophic yeast Pichia pastoris and its activity was evaluated in vitro against macrophages and in experimental atherosclerosis in Ldlr(-/-) mice. The recombinant 2C7 scFv was produced in a yield of 9.5 mg of protein/L. The specificity and affinity of purified 2C7 scFv against LDL(-) was confirmed by ELISA. To assess the activity of 2C7 scFv on foam cell formation, RAW 264.7 macrophages were exposed to LDL(-) in the presence or absence of 2C7 scFv. The 2C7 scFv inhibited the uptake of LDL(-) by macrophages in a dose-dependent manner, and internalization of LDL(-) by these cells was found to be mediated by the CD36 and CD14 receptor. In addition, compared with untreated cells, lipid accumulation in macrophages was decreased, and the expression of Cd36, Tlr-4 and Cox-2 was downregulated in macrophages treated with 2C7 scFv. Importantly, compared with untreated mice, the treatment of Ldlr(-/-) mice with 2C7 scFv decreased the atherosclerotic lesion area at the aortic sinus. In conclusion, our data show that 2C7 scFv inhibits foam cell formation and atherosclerotic plaque development by modulating the expression of genes relevant to atherogenesis. These results encourage further use of this antibody fragment in the development of new therapeutic strategies that neutralize the pro-atherogenic effects of LDL(-).

  4. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors

    PubMed Central

    Gordts, Philip L.S.M.; Son, Ni-Huiping; Ramms, Bastian; Lew, Irene; Gonzales, Jon C.; Thacker, Bryan E.; Basu, Debapriya; Lee, Richard G.; Mullick, Adam E.; Graham, Mark J.; Goldberg, Ira J.; Crooke, Rosanne M.; Witztum, Joseph L.

    2016-01-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III–targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO–induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III–rich or ApoC-III–depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis. PMID:27400128

  5. ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.

    PubMed

    Gordts, Philip L S M; Nock, Ryan; Son, Ni-Huiping; Ramms, Bastian; Lew, Irene; Gonzales, Jon C; Thacker, Bryan E; Basu, Debapriya; Lee, Richard G; Mullick, Adam E; Graham, Mark J; Goldberg, Ira J; Crooke, Rosanne M; Witztum, Joseph L; Esko, Jeffrey D

    2016-08-01

    Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.

  6. Electronegativity and the Bond Triangle

    ERIC Educational Resources Information Center

    Meek, Terry L.; Garner, Leah D.

    2005-01-01

    The usefulness of the bond triangle for categorizing compounds of the main-group elements may be extended by the use of weighted average electronegativities to allow distinction between compounds of the same elements with different stoichiometries. In such cases a higher valency for the central atom leads to greater covalent character and the…

  7. Electronegativity and the Bond Triangle

    ERIC Educational Resources Information Center

    Meek, Terry L.; Garner, Leah D.

    2005-01-01

    The usefulness of the bond triangle for categorizing compounds of the main-group elements may be extended by the use of weighted average electronegativities to allow distinction between compounds of the same elements with different stoichiometries. In such cases a higher valency for the central atom leads to greater covalent character and the…

  8. Immunization with cationized BSA inhibits progression of disease in ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis.

    PubMed

    Kolbus, Daniel; Wigren, Maria; Ljungcrantz, Irena; Söderberg, Ingrid; Alm, Ragnar; Björkbacka, Harry; Nilsson, Jan; Fredrikson, Gunilla N

    2011-06-01

    Immune responses against modified self-antigens generated by hypercholesterolemia play an important role in atherosclerosis identifying the immune system as a possible novel target for prevention and treatment of cardiovascular disease. It has recently been shown that these immune responses can be modulated by subcutaneous injection of adjuvant. In the present study we immunized 25-week old ApoBec-1/LDL receptor deficient mice with manifest atherosclerosis with adjuvant and two different concentrations of the carrier molecule cationized BSA (cBSA). Plasma levels of Th2-induced apolipoprotein B (apoB)/IgG1 immune complexes were increased in the cBSA immunized groups verifying induction of immunity against a self-antigen. Mice were sacrificed at 36 weeks of age and atherosclerosis was monitored by en face Oil red O staining of the aorta. Immunization with 100 μg cBSA inhibited plaque progression, whereas the lower dose (50 μg) did not. In addition, the higher dose induced a more stable plaque phenotype, indicated by a higher content of collagen and less macrophages and T cells in the plaques. Moreover, there was an increased ratio of Foxp3+/Foxp3⁻ T cells in the circulation suggesting activation of a regulatory T cell response. In conclusion, we show that immunization with cBSA induces an immune response against apoB as well as an activation of Treg cells. This was associated with development of a more stable plaque phenotype and reduced atherosclerosis progression.

  9. Curcumin Alleviates oxLDL Induced MMP-9 and EMMPRIN Expression through the Inhibition of NF-κB and MAPK Pathways in Macrophages

    PubMed Central

    Cao, Jiatian; Ye, Bozhi; Lin, Lu; Tian, Lei; Yang, Hongbo; Wang, Changqian; Huang, Weijian; Huang, Zhouqing

    2017-01-01

    Rupture of vulnerable atherosclerotic plaques is the leading cause of acute myocardial infarction (AMI) and unstable angina pectoris (UA). However, it still lacks an effective therapy to stabilize the vulnerable atherosclerotic plaques. Numerous reports have shown that upregulation of MMP-9 (matrix metalloproteinase-9) and EMMPRIN (extracellular matrix metalloproteinase inducer) in macrophages is involved in the progression and development of vulnerable plaques. Here we evaluated the impact of curcumin on the expression of MMP-9 and EMMPRIN in macrophages. Macrophages were pretreated with curcumin or specific inhibitors (p38 MAPK inhibitor, NF-κB p65 inhibitor) for 1 h, then cells were cultured with oxLDL for indicated time. Real-time PCR and Western blot analysis were used to evaluate the expression of mRNA and proteins. Translocation of NF-κB p65 was detected by using laser confocal microscopy. Here we showed that curcumin attenuated the MMP-9 and EMMPRIN expression in oxLDL stimulated macrophages. Further studies revealed that curcumin inhibited oxLDL induced NF-κB activation and p38 MAPK phosphorylation. These findings illustrated that curcumin can inhibit the expression of EMMPRIN and MMP-9 in oxLDL stimulated macrophages through down regulation of NF-κB and p38 MAPK signaling pathways, which might be the molecular mechanism for the anti-atherosclerotic effect of curcumin. PMID:28261097

  10. Salvianolic acid B inhibits macrophage uptake of modified low density lipoprotein (mLDL) in a scavenger receptor CD36-dependent manner

    PubMed Central

    Bao, Yi; Wang, Li; Xu, Yanni; Yang, Yuan; Wang, Lifei; Si, Shuyi; Cho, Sunghee; Hong, Bin

    2012-01-01

    CD36, a class B scavenger receptor, has been implicated in the pathogenesis of a host of vascular inflammatory diseases. Through a high-throughput screening (HTS) assay for CD36 antagonist, we previously identified salvianolic acid B (SAB), a hydrophilic component derived from the herb Danshen, as a potential candidate. Danshen, the dried roots of Salvia miltiorrhiza, has been widely used in China for the prevention and treatment of atherosclerosis-related disorders. Previous studies showed that SAB acted as an anti-oxidant by preventing lipid peroxidation and oxidized LDL (oxLDL) formation. The present study was to investigate the specificity and efficacy of SAB in the inhibition of CD36-mediated lipid uptake. SAB reduced modified LDL (mLDL) uptake in a dose-dependent manner in phorbol-12-myristate-13-acetate (PMA)-stimulated THP-1 and RAW 264.7 cells. In the CD36 silenced THP-1 cells, SAB had no effect in reducing mLDL uptake, whereas its over-expression in CHO cells reinstates the effect, indicating a specific involvement of SAB in antagonizing the CD36's function. Surface plasmon resonance (SPR) analysis revealed a direct binding of SAB to CD36 with a high affinity (KD =3.74 μM), confirming physical interactions of SAB with the receptor. Additionally, SAB reduced oxLDL-induced CD36 gene expression in the cultured cell lines and primary macrophages. In ApoE KO mice fed a high fat diet, SAB reduced CD36 gene expression and lipid uptake in macrophages, showing its ability to antagonize CD36 pathways in vivo. These results demonstrate that SAB is an effective CD36 antagonist and suggest SAB as a potential anti-atherosclerotic agent. PMID:22658257

  11. Calcium-independent inhibition of PCSK9 by affinity-improved variants of the LDL receptor EGF(A) domain.

    PubMed

    Zhang, Yingnan; Zhou, Lijuan; Kong-Beltran, Monica; Li, Wei; Moran, Paul; Wang, Jianyong; Quan, Clifford; Tom, Jeffrey; Kolumam, Ganesh; Elliott, J Michael; Skelton, Nicholas J; Peterson, Andrew S; Kirchhofer, Daniel

    2012-10-05

    LDL (low-density lipoprotein) receptor (LDLR) binds to its negative regulator proprotein convertase subtilisin/kexin type 9 (PCSK9) through the first EGF (epidermal growth factor-like) domain [EGF(A)]. The isolated EGF(A) domain is a poor antagonist due to its low affinity for PCSK9. To improve binding affinity, we used a phage display approach by randomizing seven PCSK9 contact residues of EGF(A), including the Ca(2+)-coordinating Asp310. The library was panned in Ca(2+)-free solution, and 26 unique clones that bind to PCSK9 were identified. Four selected variants demonstrated improved inhibitory activities in a PCSK9-LDLR competition binding ELISA. The Fc fusion protein of variant EGF66 bound to PCSK9 with a K(d) value of 71 nM versus 935 nM of wild type [EGF(A)-Fc] and showed significantly improved potency in inhibiting LDLR degradation in vitro and in vivo. The five mutations in EGF66 could be modeled in the EGF(A) structure without perturbation of the EGF domain fold, and their contribution to affinity improvement could be rationalized. The most intriguing change was the substitution of the Ca(2+)-coordinating Asp310 by a Lys residue, whose side-chain amine may have functionally replaced Ca(2+). EGF66-Fc and other EGF variants having the Asp310Lys change bound to PCSK9 in a Ca(2+)-independent fashion. The findings indicate that randomization of an important Ca(2+)-chelating residue in conjunction with "selection pressure" applied by Ca(2+)-free phage selection conditions can yield variants with an alternatively stabilized Ca(2+) loop and with increased binding affinities. This approach may provide a new paradigm for the use of diversity libraries to improve affinities of members of the Ca(2+)-binding EGF domain subfamily.

  12. Phenolic-extract from argan oil (Argania spinosa L.) inhibits human low-density lipoprotein (LDL) oxidation and enhances cholesterol efflux from human THP-1 macrophages.

    PubMed

    Berrougui, Hicham; Cloutier, Martin; Isabelle, Maxim; Khalil, Abdelouahed

    2006-02-01

    Argan oil is rich in unsaturated fatty acids, tocopherol and phenolic compounds. These protective molecules make further study of its cardiovascular diseases (CVDs) action interesting. Furthermore, no previous study has explored the antioxidant activity of argan oil in comparison with olive oil. The present study was conducted to evaluate the beneficial properties of Virgin argan oil phenolic extracts (VAO-PE) towards CVD by: (A) protecting human (low-density lipoprotein, LDL) against lipid peroxidation and (B) promoting high-density lipoprotein (HDL)-mediated cholesterol efflux. Human LDLs were oxidized by incubation with CuSO(4) in the presence of different concentrations of VAO-PE (0-320mug/ml). LDL lipid peroxidation was evaluated by conjugated diene and MDA formation as well as Vitamin E disappearance. Incubation of LDL with VAO-PE significantly prolonged the lag-phase and lowered the progression rate of lipid peroxidation (P<0.01) and reduced the disappearance of Vitamin E in a concentration-dependent manner. Incubation of HDL with VAO-PE significantly increased the fluidity of the HDL phospholipidic bilayer (P=0.0004) and HDL-mediated cholesterol efflux from THP-1 macrophages. These results suggest that Virgin argan oil provides a source of dietary phenolic antioxidants, which prevent cardiovascular diseases by inhibiting LDL-oxidation and enhancing reverse cholesterol transport. These properties increase the anti-atherogenic potential of HDL.

  13. Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

    PubMed

    Toma, Laura; Sanda, Gabriela M; Niculescu, Loredan S; Deleanu, Mariana; Stancu, Camelia S; Sima, Anca V

    2017-07-28

    Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL). Levels of the receptor for advanced glycation end-products (RAGE), inflammatory stress markers (C reactive protein, CRP; vascular cell adhesion molecule-1, VCAM-1; monocyte chemoattractant protein-1, MCP-1), and oxidative stress and endoplasmic reticulum stress (ERS) markers were evaluated in gLDL-exposed HEC, in the presence/absence of CAF. RAGE silencing or blocking, specific inhibitors for oxidative stress (apocynin, N-acetyl-cysteine), and ERS (salubrinal) were used. The results showed that: (i) gLDL induced CRP synthesis and secretion through mechanisms involving NADPH oxidase-dependent oxidative stress and ERS in HEC; (ii) gLDL-RAGE interaction, oxidative stress, and ERS stimulated the secretion of VCAM-1 and MCP-1 in HEC; and (iii) CAF reduced the secretion of CRP, VCAM-1, and MCP-1 in gLDL-exposed HEC by inhibiting RAGE expression, oxidative stress, and ERS. In conclusion, CAF might be a promising alternative to ameliorate a wide spectrum of disorders due to its complex mechanisms of action resulting in anti-inflammatory and antioxidative properties. © 2017 BioFactors, 2017. © 2017 International Union of Biochemistry and Molecular Biology.

  14. Thermal stability of human plasma electronegative low-density lipoprotein: A paradoxical behavior of low-density lipoprotein aggregation

    PubMed Central

    Rull, Anna; Jayaraman, Shobini; Gantz, Donald L.; Rivas-Urbina, Andrea; Pérez-Cuellar, Montserrat; Ordóñez-Llanos, Jordi; Sánchez-Quesada, Jose Luis; Gursky, Olga

    2017-01-01

    Low-density lipoprotein (LDL) aggregation is central in triggering atherogenesis. A minor fraction of electronegative plasma LDL, termed LDL(−), plays a special role in atherogenesis. To better understand this role, we analyzed the kinetics of aggregation, fusion and disintegration of human LDL and its fractions, LDL(+) and LDL(−). Thermal denaturation of LDL was monitored by spectroscopy and electron microscopy. Initially, LDL(−) aggregated and fused faster than LDL(+), but later the order reversed. Most LDL(+) disintegrated and precipitated upon prolonged heating. In contrast, LDL(−) partially retained lipoprotein morphology and formed soluble aggregates. Biochemical analysis of all fractions showed no significant degradation of major lipids, mild phospholipid oxidation, and anincrease in non-esterified fatty acid (NEFA) upon thermal denaturation. The main baseline difference between LDL subfractions was higher content of NEFA in LDL(−). Since NEFA promote lipoprotein fusion, increased NEFA content can explain rapid initial aggregation and fusion of LDL(−) but not its resistance to extensive disintegration. Partial hydrolysis of apoB upon heating was similar in LDL subfractions, suggesting that minor proteins importantly modulate LDL disintegration. Unlike LDL(+), LDL(−) contains small amounts of apoA-I and apoJ. Addition of exogenous apoA-I to LDL(+) hampered lipoprotein aggregation, fusion and precipitation, while depletion of endogenous apoJ had an opposite effect. Therefore, the initial rapid aggregation of LDL(−) is apparently counterbalanced by the stabilizing effects of minor proteins such as apoA-I and apoJ. These results help identify key determinants for LDL aggregation, fusion and coalescence into lipid droplets in vivo. PMID:27233433

  15. A complex of antioxidant vitamins effectively inhibits free-radical oxidation of LDL phospholipids in blood plasma and membrane structures of the liver and myocardium.

    PubMed

    Konovalova, G G; Lisina, M O; Tikhaze, A K; Lankin, V Z

    2003-02-01

    Antioxidant effect of a complex preparation including antioxidant vitamins C, E, provitamin A and selenium was studied on the model of Cu(2+)-initiated free-radical oxidation of LDL isolated from human blood plasma. The antioxidant effect of combined administration of alpha-tocopherol+ascorbic acid and alpha-tocopherol+beta-carotene is far more pronounced that the antioxidant effect of individual components of these cocktails. Moreover, in the model system the combined action of all antioxidant components completely inhibited free-radical oxidation of LDL. A 30-day course of peroral administration of antioxidant vitamin cocktail and selenium to rats pronouncedly enhanced the antioxidant potential of liver and completely suppressed free-radical processes in the myocardium. It is suggested that preparations containing antioxidant vitamins and selenium can be perspective for prevention and complex therapy of atherosclerosis.

  16. Revised Mulliken Electronegativities I. Calculation and Conversion to Pauling Units.

    ERIC Educational Resources Information Center

    Bratsch, Steven G.

    1988-01-01

    Discusses a revision and extension of the Mulliken electronegativity scale to consider 50 elements. Describes the calculation of valence-state promotion energies and Mulliken atomic electronegativities and the conversion of Mulliken electronegativities to Pauling units. (CW)

  17. Hypoxia worsens the impact of intracellular triglyceride accumulation promoted by electronegative low-density lipoprotein in cardiomyocytes by impairing perilipin 5 upregulation.

    PubMed

    Revuelta-López, Elena; Cal, Roi; Julve, Josep; Rull, Anna; Martínez-Bujidos, Maria; Perez-Cuellar, Montserrat; Ordoñez-Llanos, Jordi; Badimon, Lina; Sanchez-Quesada, Jose Luis; Llorente-Cortés, Vicenta

    2015-08-01

    Plasma lipoproteins are a source of lipids for the heart, and the proportion of electronegative low density lipoprotein [LDL(-)] is elevated in cardiometabolic diseases. Perilipin 5 (Plin5) is a crucial protein for lipid droplet management in the heart. Our aim was to assess the effect of LDL(-) on intracellular lipid content and Plin5 levels in cardiomyocytes and to determine whether these effects were influenced by hypoxia. HL-1 cardiomyocytes were exposed to native LDL [LDL(+)], LDL(-), and LDL(+) enriched in non-esterified fatty acids (NEFA) by phospholipase A2 (PLA2)-mediated lipolysis [PLA2-LDL(+)] or by NEFA loading [NEFA-LDL(+)] under normoxia or hypoxia. LDL(-), PLA2-LDL(+) and NEFA-LDL(+) raised the intracellular NEFA and triglyceride (TG) content of normoxic cardiomyocytes. Plin5 was moderately upregulated by LDL(+) but more highly upregulated by LDL(-), PLA2-LDL(+) and NEFA-LDL(+) in normoxic cardiomyocytes. Hypoxia enhanced the effect of LDL(-), PLA2-LDL(+) and NEFA-LDL(+) on intracellular TG and NEFA concentrations but, in contrast, counteracted the upregulatory effect of these LDLs on Plin5. Fluorescence microscopy experiments showed that hypoxic cardiomyocytes exposed to LDL(-), PLA2-LDL(+) and NEFA-LDL(+) have an increased production of reactive oxygen species (ROS). By treating hypoxic cardiomyocytes with WY-14643 (PPARα agonist), Plin5 remained high. In this situation, LDL(-) failed to enhance intracellular NEFA concentration and ROS production. In conclusion, these results show that Plin5 deficiency in hypoxic cardiomyocytes exposed to LDL(-) dramatically increases the levels of unpacked NEFA and ROS.

  18. Deuterium kinetic isotope effect (DKIE) in copper-induced LDL peroxidation: Interrelated effects of on inhibition and propagation.

    PubMed

    Pinchuk, Ilya; Lichtenberg, Dov

    2017-06-01

    LDL peroxidation plays a major role in many physiological and pathophysiological processes. The mechanisms of LDL peroxidation induced by transition metal ions have therefore been studied intensively. It has been proposed that the mechanism involves free radical production that occurs via decomposition of hydroperoxides. This, in turn, requires the cleavage of O-H bonds. Cleavage of O-D bond is slower and comparison of the kinetics in D2O to the kinetics in H2O is therefore a straightforward way to test this aspect of the alleged mechanism. The kinetics of peroxidation exhibit marked deuterium kinetic isotope effects at all the stages of oxidation under all the studied conditions. We found that the rate of propagation of copper-induced peroxidation is a monotonically decreasing function of D2O fraction in D2O/H2O mixtures. The only elementary reaction that involves "exchangeable" hydrogen at this stage is copper-induced decomposition of conjugated hydroperoxides. Therefore, we conclude that the latter step is rate-limiting reaction including cleavage of oxygen-hydrogen bond of hydroperoxide. The lag preceding rapid peroxidation exhibits a biphasic dependence on the fraction of D2O. This may be understood on the basis of the effect of substituting hydrogen atoms by deuterium. Specifically, such substitution is expected to decrease both the rate of initiation of peroxidation and the potency of the antioxidant. We interpret our results in terms of the effects of isotopic substitution on the rates of the reactions that involve the abstraction of "exchangeable" hydrogen atoms of OH groups in tocopherol and hydroperoxides. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. The Quantification of Electronegativity: Some Precursors

    ERIC Educational Resources Information Center

    Jensen, William B.

    2012-01-01

    This paper calls attention to the early work of the American chemists Worth Rodebush and Groves Cartledge, and their anticipations of a quantitative electronegativity scale, which predate the classic 1932 paper of Linus Pauling by several years. (Contains 2 figures.)

  20. Cholesterol metabolism, LDL, and the LDL receptor

    SciTech Connect

    Myant, N.B. )

    1990-01-01

    This book covers cholesterol and metabolism. Paper include: The LDL Receptor in Perspective, Cholesterol in Animal Tissues, HMG-CoA Reductase. acetyl-CoA: Cholesterol Acyltransferase, and LDL: Physical and Chemical Characteristics.

  1. LDL Particle Testing

    MedlinePlus

    ... tests: HDL Cholesterol ; LDL Cholesterol ; Direct LDL Cholesterol ; Lipid Profile ; Cholesterol ; Apo A-I ; Apo B ; Lp(a) ; ... is typically done along with or following a lipid profile . While for many people, the LDL-C test ...

  2. Coffee drinking induces incorporation of phenolic acids into LDL and increases the resistance of LDL to ex vivo oxidation in humans.

    PubMed

    Natella, Fausta; Nardini, Mirella; Belelli, Federica; Scaccini, Cristina

    2007-09-01

    Epidemiologic and intervention studies indicate that both diet as a whole and single dietary components are involved in the risk of atherosclerosis. The resistance of LDL to oxidative modification is an ex vivo indicator of risk, which is modulated by dietary components. Coffee contains phenolic compounds with antioxidant activity. These molecules are found in plasma after the consumption of coffee, and it has been shown that, in vitro, they are able to decrease the susceptibility of LDL to oxidation. The aim of this study was to evaluate the effect of coffee consumption on the redox status of LDL as modulated by the possible incorporation of phenolic acids into LDL. Ten healthy volunteers, after an overnight fast, drank 200 mL filtered coffee. Blood was drawn before and 30 and 60 min after drinking. Changes in LDL redox status were evaluated by the measure of LDL resistance to oxidative modification and the concentration of LDL(-), a mildly modified, electronegative LDL subfraction. Chlorogenic and phenolic acids concentration in LDL were measured by electrochemical HPLC. The resistance of LDL to oxidative modification increased significantly after coffee drinking, but the LDL(-) concentration did not increase. The concentration into LDL of conjugated forms of caffeic, p-coumaric, and ferulic acids increased significantly after coffee drinking. Drinking 200 mL (1 cup) coffee induces an increase in the resistance of LDL to oxidative modification, probably as a result of the incorporation of coffee's phenolic acids into LDL.

  3. Non-Lethal Sonodynamic Therapy Inhibits Atherosclerotic Plaque Progression in ApoE-/- Mice and Attenuates ox-LDL-mediated Macrophage Impairment by Inducing Heme Oxygenase-1.

    PubMed

    Wang, Yu; Wang, Wei; Xu, Haobo; Sun, Yan; Sun, Jing; Jiang, Yongxing; Yao, Jianting; Tian, Ye

    2017-01-01

    Previous studies from our group showed that low-intensity sonodynamic therapy (SDT) has protective effects on atherosclerosis (AS). However, because the intensity of ultrasound passing through tissue is attenuated, the consequences of very low-intensity SDT, referred to as non-lethal SDT (NL-SDT), on atherosclerotic plaques are unclear. The aim of this study was to determine whether NL-SDT affects atherosclerotic plaques and to elucidate the possible underlying mechanisms. An AS model was established using ApoE-/- mice fed a western diet. En face Oil Red O staining was used to measure atherosclerotic plaque size. Hematoxylin and eosin staining and immunohistochemical staining were used to observe plaque morphology and assess the location of macrophages and heme oxygenase 1 (HO-1). HO-1 mRNA and protein levels in AS plaques were evaluated by real-time PCR and western blotting. Human THP-1 cells and mouse peritoneal macrophages were used in this study. Western blotting was used to investigate the expression of cellular proteins after NL-SDT. Macrophage apoptosis was evaluated by TUNEL assays and flow cytometry with Annexin V/PI double staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured with 2'-7'-dichlorofluorescein diacetate (DCFH-DA) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl benzimidazolyl carbocyanine iodide (JC-1) staining, respectively. NL-SDT significantly inhibited AS progression and reduced the necrotic core area. NL-SDT induced HO-1 expression in lesional macrophages and in cultured macrophages. NL-SDT activated the protein kinase B (AKT) and extracellular signal-related protein kinase (ERK) pathways and the transcription factor NF-E2-related factor 2 (Nrf2).NL-SDT significantly reduced oxidized LDL (ox-LDL)-induced macrophage MMP collapse, ROS production and cell apoptosis. Zinc protoporphyrin (ZnPP), a HO-1-specific inhibitor, reversed the protective effects of NL-SDT. NL-SDT inhibits

  4. Narrow gap electronegative capacitive discharges

    SciTech Connect

    Kawamura, E.; Lieberman, M. A.; Lichtenberg, A. J.

    2013-10-15

    Narrow gap electronegative (EN) capacitive discharges are widely used in industry and have unique features not found in conventional discharges. In this paper, plasma parameters are determined over a range of decreasing gap length L from values for which an electropositive (EP) edge exists (2-region case) to smaller L-values for which the EN region connects directly to the sheath (1-region case). Parametric studies are performed at applied voltage V{sub rf}=500 V for pressures of 10, 25, 50, and 100 mTorr, and additionally at 50 mTorr for 1000 and 2000 V. Numerical results are given for a parallel plate oxygen discharge using a planar 1D3v (1 spatial dimension, 3 velocity components) particle-in-cell (PIC) code. New interesting phenomena are found for the case in which an EP edge does not exist. This 1-region case has not previously been investigated in detail, either numerically or analytically. In particular, attachment in the sheaths is important, and the central electron density n{sub e0} is depressed below the density n{sub esh} at the sheath edge. The sheath oscillations also extend into the EN core, creating an edge region lying within the sheath and not characterized by the standard diffusion in an EN plasma. An analytical model is developed using minimal inputs from the PIC results, and compared to the PIC results for a base case at V{sub rf}=500 V and 50 mTorr, showing good agreement. Selected comparisons are made at the other voltages and pressures. A self-consistent model is also developed and compared to the PIC results, giving reasonable agreement.

  5. Point mutations at the catalytic site of PCSK9 inhibit folding, autoprocessing, and interaction with the LDL receptor.

    PubMed

    Garvie, Colin W; Fraley, Cara V; Elowe, Nadine H; Culyba, Elizabeth K; Lemke, Christopher T; Hubbard, Brian K; Kaushik, Virendar K; Daniels, Douglas S

    2016-11-01

    Circulating low-density lipoprotein cholesterol (LDLc) is regulated by membrane-bound LDL receptor (LDLr). Upon LDLc and LDLr interaction the complex is internalized by the cell, leading to LDLc degradation and LDLr recycling back to the cell surface. The proprotein convertase subtilisin/kexin type 9 (PCSK9) protein regulates this cycling. PCSK9 is secreted from the cell and binds LDLr. When the complex is internalized, PCSK9 prevents LDLr from shuttling back to the surface and instead targets it for degradation. PCSK9 is a serine protease expressed as a zymogen that undergoes autoproteolysis, though the two resulting protein domains remain stably associated as a heterodimer. This PCSK9 autoprocessing is required for the protein to be secreted from the cell. To date, direct analysis of PCSK9 autoprocessing has proven challenging, as no catalytically active zymogen has been isolated. A PCSK9 loss-of-function point mutation (Q152H) that reduces LDLc levels two-fold was identified in a patient population. LDLc reduction was attributed to a lack of PCSK9(Q152H) autoprocessing preventing secretion of the protein. We have isolated a zymogen form of PCSK9, PCSK9(Q152H), and a related mutation (Q152N), that can undergo slow autoproteolysis. We show that the point mutation prevents the formation of the mature form of PCSK9 by hindering folding, reducing the rate of autoproteolysis, and destabilizing the heterodimeric form of the protein. In addition, we show that the zymogen form of PCSK9 adopts a structure that is distinct from the processed form and is unable to bind a mimetic peptide based on the EGF-A domain of the LDLr.

  6. Malaysian brown seaweeds Sargassum siliquosum and Sargassum polycystum: Low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase inhibition activities.

    PubMed

    Nagappan, Hemlatha; Pee, Poh Ping; Kee, Sandra Hui Yin; Ow, Ji Tsong; Yan, See Wan; Chew, Lye Yee; Kong, Kin Weng

    2017-09-01

    Two Malaysian brown seaweeds, Sargassum siliquosum and Sargassum polycystum were first extracted using methanol to get the crude extract (CE) and further fractionated to obtain fucoxanthin-rich fraction (FRF). Samples were evaluated for their phenolic, flavonoid, and fucoxanthin contents, as well as their inhibitory activities towards low density lipoprotein (LDL) oxidation, angiotensin converting enzyme (ACE), α-amylase, and α-glucosidase. In LDL oxidation assay, an increasing trend in antioxidant activity was observed as the concentration of FRF (0.04-0.2mg/mL) and CE (0.2-1.0mg/mL) increased, though not statistically significant. As for serum oxidation assay, significant decrease in antioxidant activity was observed as concentration of FRF increased, while CE showed no significant difference in inhibitory activity across the concentrations used. The IC50 values for ACE inhibitory activity of CE (0.03-0.42mg/mL) were lower than that of FRF (0.94-1.53mg/mL). When compared to reference drug Voglibose (IC50 value of 0.61mg/mL) in the effectiveness in inhibiting α-amylase, CE (0.58mg/mL) gave significantly lower IC50 values while FRF (0.68-0.71mg/mL) had significantly higher IC50 values. The α-glucosidase inhibitory activity of CE (IC50 value of 0.57-0.69mg/mL) and FRF (IC50 value of 0.50-0.53mg/mL) were comparable to that of reference drug (IC50 value of 0.54mg/mL). Results had shown the potential of S. siliquosum and S. polycystum in reducing cardiovascular diseases related risk factors following their inhibitory activities on ACE, α-amylase and α-glucosidase. In addition, it is likelihood that FRF possessed antioxidant activity at low concentration level. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. Chemical Structures of 4-Oxo-Flavonoids in Relation to Inhibition of Oxidized Low-Density Lipoprotein (LDL)-Induced Vascular Endothelial Dysfunction

    PubMed Central

    Yi, Long; Jin, Xin; Chen, Chun-Ye; Fu, Yu-Jie; Zhang, Ting; Chang, Hui; Zhou, Yong; Zhu, Jun-Dong; Zhang, Qian-Yong; Mi, Man-Tian

    2011-01-01

    Vascular endothelial dysfunction induced by oxidative stress has been demonstrated to be the initiation step of atherosclerosis (AS), and flavonoids may play an important role in AS prevention and therapy. Twenty-three flavonoids categorized into flavones, flavonols, isoflavones, and flavanones, all with 4-oxo-pyronenucleus, were examined for what structural characteristics are required for the inhibitory effects on endothelial dysfunction induced by oxidized low-density lipoprotein (oxLDL). Human vascular endothelial cells EA.hy926 were pretreated with different 4-oxo-flavonoids for 2 hs, and then exposed to oxLDL for another 24 hs. Cell viability and the level of malondialdehyde (MDA), nitric oxide (NO) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured, respectively. Then, correlation analysis and paired comparison were used to analyze the structure–activity relationships. Significant correlations were observed between the number of −OH moieties in total or in B-ring and the inhibitory effectson endothelial dysfunction. Furthermore, 3′,4′-ortho-dihydroxyl on B-ring, 3-hydroxyl on C-ring and 2,3-double bondwere correlated closely to the inhibitory effects of flavonolson cell viability decrease and lipid peroxidation. 5,7-meta-dihydroxyl group on A-ring was crucial for the anti-inflammatory effects of flavones and isoflavones in endothelial cells. Moreover, the substituted position of B-ring on C3 rather than C2 was important for NO release. Additionally, hydroxylation at C6 position significantly attenuated the inhibitory effects of 4-oxo-flavonoids on endothelial dysfunction. Our findings indicated that the effective agents in inhibiting endothelial dysfunction include myricetin, quercetin, luteolin, apigenin, genistein and daidzein. Our work might provide some evidence for AS prevention and a strategy for the design of novel AS preventive agents. PMID:22016603

  8. Chemical structures of 4-oxo-flavonoids in relation to inhibition of oxidized low-density lipoprotein (LDL)-induced vascular endothelial dysfunction.

    PubMed

    Yi, Long; Jin, Xin; Chen, Chun-Ye; Fu, Yu-Jie; Zhang, Ting; Chang, Hui; Zhou, Yong; Zhu, Jun-Dong; Zhang, Qian-Yong; Mi, Man-Tian

    2011-01-01

    Vascular endothelial dysfunction induced by oxidative stress has been demonstrated to be the initiation step of atherosclerosis (AS), and flavonoids may play an important role in AS prevention and therapy. Twenty-three flavonoids categorized into flavones, flavonols, isoflavones, and flavanones, all with 4-oxo-pyronenucleus, were examined for what structural characteristics are required for the inhibitory effects on endothelial dysfunction induced by oxidized low-density lipoprotein (oxLDL). Human vascular endothelial cells EA.hy926 were pretreated with different 4-oxo-flavonoids for 2 hs, and then exposed to oxLDL for another 24 hs. Cell viability and the level of malondialdehyde (MDA), nitric oxide (NO) and soluble intercellular adhesion molecule-1 (sICAM-1) were measured, respectively. Then, correlation analysis and paired comparison were used to analyze the structure-activity relationships. Significant correlations were observed between the number of -OH moieties in total or in B-ring and the inhibitory effectson endothelial dysfunction. Furthermore, 3',4'-ortho-dihydroxyl on B-ring, 3-hydroxyl on C-ring and 2,3-double bondwere correlated closely to the inhibitory effects of flavonolson cell viability decrease and lipid peroxidation. 5,7-meta-dihydroxyl group on A-ring was crucial for the anti-inflammatory effects of flavones and isoflavones in endothelial cells. Moreover, the substituted position of B-ring on C3 rather than C2 was important for NO release. Additionally, hydroxylation at C6 position significantly attenuated the inhibitory effects of 4-oxo-flavonoids on endothelial dysfunction. Our findings indicated that the effective agents in inhibiting endothelial dysfunction include myricetin, quercetin, luteolin, apigenin, genistein and daidzein. Our work might provide some evidence for AS prevention and a strategy for the design of novel AS preventive agents.

  9. Electronegative Guests in CoSb3

    DOE PAGES

    Duan, Bo; Yang, Jiong; Salvador, James R.; ...

    2016-04-19

    Introducing guests into a host framework to form a so called inclusion compound can be used to design materials with new and fascinating functionalities. The vast majority of inclusion compounds have electropositive guests with neutral or negatively charged frameworks. Here, we show a series of electronegative guest filled skutterudites with inverse polarity. The strong covalent guest-host interactions observed for the electronegative group VIA guests, i.e., S and Se, feature a unique localized cluster vibration which significantly influences the lattice dynamics, together with the point-defect scattering caused by element substitutions, resulting in very low lattice thermal conductivity values. The findings ofmore » electronegative guests provide a new perspective for guest-filling in skutterudites, and the covalent filler/lattice interactions lead to an unusual lattice dynamics phenomenon which can be used for designing high-efficiency thermoelectric materials and novel functional inclusion compounds with open structures.« less

  10. Generalized Bohm Criterion for Electronegative Complex Plasma

    SciTech Connect

    Chekour, S.; Tahraoui, A.

    2011-11-29

    In this work, we have generalized the computation of Bohm criterion for electronegative complex plasma. For this, we have established a one-dimensional, unmagnetized and stationary theoretical model where the positive ions and dust particles are modeled by fluid equations. The electrons and negative ions are considered in thermodynamic equilibrium; therefore they obey to Boltzmann's statistic. In this case, the numerical results show that the generalized Bohm velocity is small compared to the classical value. For electronegative dusty plasma, the corrections are less important.

  11. Nonplanar waves with electronegative dusty plasma

    SciTech Connect

    Zobaer, M. S.; Mukta, K. N.; Nahar, L.; Mamun, A. A.; Roy, N.

    2013-04-15

    A rigorous theoretical investigation has been made of basic characteristics of the nonplanar dust-ion-acoustic shock and solitary waves in electronegative dusty plasma containing Boltzmann electrons, Boltzmann negative ions, inertial positive ions, and charge fluctuating (negatively charged) stationary dust. The Burgers' and Korteweg-de Vries (K-dV) equations, which is derived by reductive perturbation technique, is numerically solved to examine the effects of nonplanar geometry on the basic features of the DIA shock and solitary waves formed in the electronegative dusty plasma. The implications of the results (obtained from this investigation) in space and laboratory experiments are briefly discussed.

  12. Merit of ground-state electronegativities; a reply to ``Comments on `Introduction to the chemistry of fractionally charged atoms: Electronegativity' ''

    NASA Astrophysics Data System (ADS)

    Lackner, Klaus S.; Zweig, George

    1987-09-01

    The arguments presented in the Comment by Liebman and Huheey are shown to be incorrect. The operational equivalence of Mulliken ground-state electronegativities and Pauling electronegativities is demonstrated for neutral atoms. It is shown that ground-state electronegativities and valence-state electronegativities for both neutral atoms and ions are also operationally equivalent. A single electronegativity scale based on Mulliken ground-state electronegativities may therefore be used for neutral atoms, ions, and fractionally charged atoms, as originally implied in the paper by Lackner and Zweig.

  13. Electronegativity from Avogadro to Pauling. Part I: Origins of the Electronegativity Concept.

    ERIC Educational Resources Information Center

    Jensen, William B.

    1996-01-01

    Discusses the origins of electronegativity as a qualitative concept in the period between 1809 and 1813. Outlines the contributions of Amedeo Avogadro and Jons Jakob Berzelius to the development of this concept. Contains 53 references. (JRH)

  14. Electronegativity from Avogadro to Pauling. Part I: Origins of the Electronegativity Concept.

    ERIC Educational Resources Information Center

    Jensen, William B.

    1996-01-01

    Discusses the origins of electronegativity as a qualitative concept in the period between 1809 and 1813. Outlines the contributions of Amedeo Avogadro and Jons Jakob Berzelius to the development of this concept. Contains 53 references. (JRH)

  15. A New Method of Estimating Atomic Charges by Electronegativity Equilibration.

    ERIC Educational Resources Information Center

    Smith, Derek W.

    1990-01-01

    Presented is a modification of Bratsch's prescription so that difficult problems are obviated while simple, familiar Pauling electronegativities are retained. Discussed are the equilibration of electronegativity in molecules, group electronegativities, coordination compounds and molecules with dative bonds, ions, and correlation with core…

  16. A New Method of Estimating Atomic Charges by Electronegativity Equilibration.

    ERIC Educational Resources Information Center

    Smith, Derek W.

    1990-01-01

    Presented is a modification of Bratsch's prescription so that difficult problems are obviated while simple, familiar Pauling electronegativities are retained. Discussed are the equilibration of electronegativity in molecules, group electronegativities, coordination compounds and molecules with dative bonds, ions, and correlation with core…

  17. LDL Cholesterol Test

    MedlinePlus

    ... Lipoprotein Cholesterol Related tests: Cholesterol ; HDL Cholesterol ; Triglycerides ; Lipid Profile ; Direct LDL Cholesterol ; Cardiac Risk Assessment ; Lp(a) ; ... LDL-C) is used as part of a lipid profile to predict an individual's risk of developing heart ...

  18. The LDL receptor.

    PubMed

    Goldstein, Joseph L; Brown, Michael S

    2009-04-01

    In this article, the history of the LDL receptor is recounted by its codiscoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life.

  19. Instabilities in Inductive Discharges with Electronegative Gases

    DTIC Science & Technology

    2003-07-20

    electronegative gases P. Chabert, H . Abada , and J.-P. Booth LPTP, Ecole Polytechnique, 91128 Palaiseau cedex, France A.J. Lichtenberg, M.A. Lieberman, A. M...can exist in two inductive discharge modes: the capacitive (E) mode, for low power, and the g00 inductive ( H ) mode, for high power. As the power is -1...increased, transitions from capacitive to inductive modes D00 (E- H transitions) are observed [7,8]. When operating with Q. electropositive gases the

  20. H2 inhibits TNF-α-induced lectin-like oxidized LDL receptor-1 expression by inhibiting nuclear factor κB activation in endothelial cells.

    PubMed

    Song, Guohua; Tian, Hua; Liu, Jia; Zhang, Hongle; Sun, Xuejun; Qin, Shucun

    2011-09-01

    H(2) is a therapeutic antioxidant that can reduce oxidative stress. Oxidized low-density lipoprotein, which plays roles in atherosclerosis, may promote endothelial dysfunction by binding the cell-surface receptor LOX-1. LOX-1 expression can be upregulated by various stimuli, including TNF-α. Thus, we aimed to examine whether the upregulation of LOX-1 by different stimuli could be blocked by H(2) in endothelial cells. H(2) significantly abolished the upregulation of LOX-1 by different stimuli, including TNF-α, at the protein and mRNA levels. The TNF-α-induced upregulation of LOX-1 was also attenuated by the NF-κB inhibitor N-acetyl-L-cysteine. H(2) inhibited the TNF-α-induced activation of NF-κB and the phosphorylation of IκB-α. Furthermore, H(2) inhibited the expression of LOX-1 and the activation of NF-κB in apolipoprotein E knockout mice, an animal model of atherosclerosis. Thus, H(2) probably inhibits cytokine-induced LOX-1 gene expression by suppressing NF-κB activation.

  1. Inhibition of the NF-κB pathway by R65 ribozyme gene via adeno-associatedvirus serotype 9 ameliorated oxidized LDL induced human umbilical vein endothelial cell injury

    PubMed Central

    Zhai, Hui; Chen, Qing-Jie; Gao, Xiao-Ming; Ma, Yi-Tong; Chen, Bang-Dang; Yu, Zi-Xiang; Li, Xiao-Mei; Liu, Fen; Xiang, Yang; Xie, Jia; Yang, Yi-Ning

    2015-01-01

    Objective: NF-κB signaling plays a central role in the regulation of inflammatory responses in atherosclerosis. R65 ribozyme gene suppresses activation of NF-κB pathway, therefore we studied whether R65 gene therapy can ameliorate oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) injury. Methods and results: Recombinant adeno-associated virus serotype 9 (rAVV9) vector was used to transfect the R65 ribozyme gene (rAVV9-R65) into HUVECs then following ox-LDL stimulation, expression of NF-κB p65 and p50 subunits, inflammatory mediators and cell apoptosis were examined. First, rAVV9-enhanced green fluorescent protein (eGFP)-R65 at 1×107 v.g./cell multiplicity of infection reached a long-lasting and significant increase in R65 gene expression. Second, ox-LDL treatment led to time- and dose-dependent activation of NF-κB pathway, and enhanced inflammatory response and cell death evidenced by increased expression of nuclear NF-κB p65 and p50 subunits, greater production of tumor necrosis factor α, interleukin-6 and von willebrand factor and 20.57% increasedapoptotic HUVECs. Third, over-expression ofR65 gene was 2-fold increased in HUVECs attenuated ox-LDL induced unclear accumulation and expression of p65 subunit and ameliorated inflammation and cell death (all P < 0.05). Conclusion: rAAV9-mediated R65 ribozyme gene transfection in cultured HUVECs effectively inhibits ox-LDL induced activation of NF-κB and production of inflammatory cytokines and prevents cell apoptosis. PMID:26617700

  2. Inhibition of the NF-κB pathway by R65 ribozyme gene via adeno-associated virus serotype 9 ameliorated oxidized LDL induced human umbilical vein endothelial cell injury.

    PubMed

    Zhai, Hui; Chen, Qing-Jie; Gao, Xiao-Ming; Ma, Yi-Tong; Chen, Bang-Dang; Yu, Zi-Xiang; Li, Xiao-Mei; Liu, Fen; Xiang, Yang; Xie, Jia; Yang, Yi-Ning

    2015-01-01

    NF-κB signaling plays a central role in the regulation of inflammatory responses in atherosclerosis. R65 ribozyme gene suppresses activation of NF-κB pathway, therefore we studied whether R65 gene therapy can ameliorate oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs) injury. Recombinant adeno-associated virus serotype 9 (rAVV9) vector was used to transfect the R65 ribozyme gene (rAVV9-R65) into HUVECs then following ox-LDL stimulation, expression of NF-κB p65 and p50 subunits, inflammatory mediators and cell apoptosis were examined. First, rAVV9-enhanced green fluorescent protein (eGFP)-R65 at 1×10(7) v.g./cell multiplicity of infection reached a long-lasting and significant increase in R65 gene expression. Second, ox-LDL treatment led to time- and dose-dependent activation of NF-κB pathway, and enhanced inflammatory response and cell death evidenced by increased expression of nuclear NF-κB p65 and p50 subunits, greater production of tumor necrosis factor α, interleukin-6 and von willebrand factor and 20.57% increased apoptotic HUVECs. Third, over-expression of R65 gene was 2-fold increased in HUVECs attenuated ox-LDL induced unclear accumulation and expression of p65 subunit and ameliorated inflammation and cell death (all P < 0.05). rAAV9-mediated R65 ribozyme gene transfection in cultured HUVECs effectively inhibits ox-LDL induced activation of NF-κB and production of inflammatory cytokines and prevents cell apoptosis.

  3. Langmuir probe analysis in electronegative plasmas

    SciTech Connect

    Bredin, Jerome Chabert, Pascal; Aanesland, Ane

    2014-12-15

    This paper compares two methods to analyze Langmuir probe data obtained in electronegative plasmas. The techniques are developed to allow investigations in plasmas, where the electronegativity α{sub 0} = n{sub –}/n{sub e} (the ratio between the negative ion and electron densities) varies strongly. The first technique uses an analytical model to express the Langmuir probe current-voltage (I-V) characteristic and its second derivative as a function of the electron and ion densities (n{sub e}, n{sub +}, n{sub –}), temperatures (T{sub e}, T{sub +}, T{sub –}), and masses (m{sub e}, m{sub +}, m{sub –}). The analytical curves are fitted to the experimental data by adjusting these variables and parameters. To reduce the number of fitted parameters, the ion masses are assumed constant within the source volume, and quasi-neutrality is assumed everywhere. In this theory, Maxwellian distributions are assumed for all charged species. We show that this data analysis can predict the various plasma parameters within 5–10%, including the ion temperatures when α{sub 0} > 100. However, the method is tedious, time consuming, and requires a precise measurement of the energy distribution function. A second technique is therefore developed for easier access to the electron and ion densities, but does not give access to the ion temperatures. Here, only the measured I-V characteristic is needed. The electron density, temperature, and ion saturation current for positive ions are determined by classical probe techniques. The electronegativity α{sub 0} and the ion densities are deduced via an iterative method since these variables are coupled via the modified Bohm velocity. For both techniques, a Child-Law sheath model for cylindrical probes has been developed and is presented to emphasize the importance of this model for small cylindrical Langmuir probes.

  4. Electronegativity from Avogadro to Pauling: II. Late Nineteenth- and Early Twentieth-Century Developments.

    ERIC Educational Resources Information Center

    Jensen, William B.

    2003-01-01

    Traces electronegativity in four fundamental areas of chemistry during the period 1870-1910: (1) the relationship between electronegativity and classical valence; (2) the relationship between electronegativity and periodic law; (3) the relationship between electronegativity thermochemistry; and (4) the relationship between electronegativity and…

  5. Electronegativity from Avogadro to Pauling: II. Late Nineteenth- and Early Twentieth-Century Developments.

    ERIC Educational Resources Information Center

    Jensen, William B.

    2003-01-01

    Traces electronegativity in four fundamental areas of chemistry during the period 1870-1910: (1) the relationship between electronegativity and classical valence; (2) the relationship between electronegativity and periodic law; (3) the relationship between electronegativity thermochemistry; and (4) the relationship between electronegativity and…

  6. Electronegative Gas Thruster - Direct Thrust Measurement Project

    NASA Technical Reports Server (NTRS)

    Dankanich, John (Principal Investigator); Aanesland, Ane; Polzin, Kurt; Walker, Mitchell

    2015-01-01

    This effort is an international collaboration and academic partnership to mature an innovative electric propulsion (EP) thruster concept to TRL 3 through direct thrust measurement. The initial target application is for Small Satellites, but can be extended to higher power. The Plasma propulsion with Electronegative GASES (PEGASES) concept simplifies ion thruster operation, eliminates a neutralizer requirement and should yield longer life capabilities and lower cost implementation over conventional gridded ion engines. The basic proof-of concept has been demonstrated and matured to TRL 2 over the past several years by researchers at the Laboratoire de Physique des Plasma in France. Due to the low maturity of the innovation, there are currently no domestic investments in electronegative gas thrusters anywhere within NASA, industry or academia. The end product of this Center Innovation Fund (CIF) project will be a validation of the proof-of-concept, maturation to TRL 3 and technology assessment report to summarize the potential for the PEGASES concept to supplant the incumbent technology. Information exchange with the foreign national will be one-way with the exception of the test results. Those test results will first go through a standard public release ITAR/export control review, and the results will be presented in a public technical forum, and the results will be presented in a public technical forum.

  7. Montelukast inhibits oxidized low-density lipoproteins (ox-LDL) induced vascular endothelial attachment: An implication for the treatment of atherosclerosis.

    PubMed

    Di, Xiuhua; Tang, Xuelu; Di, Xiuting

    2017-04-22

    Recruitment of monocytes to endothelial cells is important during early stages of atherosclerosis development, which is activated in response to a number of inflammatory stimuli, including oxidized low-density lipoprotein (ox-LDL). Montelukast is a licensed drug approved by the Food and Drug Administration (FDA) and clinically used for the treatment of asthma by reducing the eosinophilic inflammation in the airway. Little information regarding the effects of Montelukast on endothelial inflammation has been reported before. In the current study, we found that Montelukast markedly reduced ox-LDL-induced monocyte adhesion to human umbilical vein endothelial cells. In addition, the inhibitory mechanism of Montelukast was associated with suppression of adhesion molecule expression, including VCAM-1 and E-selectin. Mechanistically, ERK5 mediated expression of the transcriptional factor KLF2 was found to be involved in the anti-inflammation effects of Montelukast against ox-LDL induced endothelial inflammation. Results indicate that Montelukast plays a protective role in the early stages of atherosclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. oxLDL induces endothelial cell proliferation via Rho/ROCK/Akt/p27(kip1) signaling: opposite effects of oxLDL and cholesterol loading.

    PubMed

    Zhang, Chongxu; Adamos, Crystal; Oh, Myung-Jin; Baruah, Jugajyoti; Ayee, Manuela A A; Mehta, Dolly; Wary, Kishore K; Levitan, Irena

    2017-09-01

    Oxidized modifications of LDL (oxLDL) play a key role in the development of endothelial dysfunction and atherosclerosis. However, the underlying mechanisms of oxLDL-mediated cellular behavior are not completely understood. Here, we compared the effects of two major types of oxLDL, copper-oxidized LDL (Cu(2+)-oxLDL) and lipoxygenase-oxidized LDL (LPO-oxLDL), on proliferation of human aortic endothelial cells (HAECs). Cu(2+)-oxLDL enhanced HAECs' proliferation in a dose- and degree of oxidation-dependent manner. Similarly, LPO-oxLDL also enhanced HAEC proliferation. Mechanistically, both Cu(2+)-oxLDL and LPO-oxLDL enhance HAEC proliferation via activation of Rho, Akt phosphorylation, and a decrease in the expression of cyclin-dependent kinase inhibitor 1B (p27(kip1)). Both Cu(2+)-oxLDL or LPO-oxLDL significantly increased Akt phosphorylation, whereas an Akt inhibitor, MK2206, blocked oxLDL-induced increase in HAEC proliferation. Blocking Rho with C3 or its downstream target ROCK with Y27632 significantly inhibited oxLDL-induced Akt phosphorylation and proliferation mediated by both Cu(2+)- and LPO-oxLDL. Activation of RhoA was blocked by Rho-GDI-1, which also abrogated oxLDL-induced Akt phosphorylation and HAEC proliferation. In contrast, blocking Rac1 in these cells had no effect on oxLDL-induced Akt phosphorylation or cell proliferation. Moreover, oxLDL-induced Rho/Akt signaling downregulated cell cycle inhibitor p27(kip1) Preloading these cells with cholesterol, however, prevented oxLDL-induced Akt phosphorylation and HAEC proliferation. These findings provide a new understanding of the effects of oxLDL on endothelial proliferation, which is essential for developing new treatments against neovascularization and progression of atherosclerosis. Copyright © 2017 the American Physiological Society.

  9. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes

    PubMed Central

    2013-01-01

    Background Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. Methods One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. Results Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. Conclusions The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition. PMID:23915379

  10. Impact of the LDL subfraction phenotype on Lp-PLA2 distribution, LDL modification and HDL composition in type 2 diabetes.

    PubMed

    Sánchez-Quesada, Jose Luis; Vinagre, Irene; De Juan-Franco, Elena; Sánchez-Hernández, Juan; Bonet-Marques, Rosa; Blanco-Vaca, Francisco; Ordóñez-Llanos, Jordi; Pérez, Antonio

    2013-08-05

    Qualitative alterations of lipoproteins underlie the high incidence of atherosclerosis in diabetes. The objective of this study was to assess the impact of low-density lipoprotein (LDL) subfraction phenotype on the qualitative characteristics of LDL and high-density lipoprotein (HDL) in patients with type 2 diabetes. One hundred twenty two patients with type 2 diabetes in poor glycemic control and 54 healthy subjects were included in the study. Patients were classified according to their LDL subfraction phenotype. Seventy-seven patients presented phenotype A whereas 45 had phenotype B. All control subjects showed phenotype A. Several forms of modified LDL, HDL composition and the activity and distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) were analyzed. Oxidized LDL, glycated LDL and electronegative LDL were increased in both groups of patients compared with the control group. Patients with phenotype B had increased oxidized LDL and glycated LDL concentration than patients with phenotype A. HDL composition was abnormal in patients with diabetes, being these abnormalities more marked in patients with phenotype B. Total Lp-PLA2 activity was higher in phenotype B than in phenotype A or in control subjects. The distribution of Lp-PLA2 between HDL and apoB-containing lipoproteins differed in patients with phenotype A and phenotype B, with higher activity associated to apoB-containing lipoproteins in the latter. The presence of LDL subfraction phenotype B is associated with increased oxidized LDL, glycated LDL and Lp-PLA2 activity associated to apoB-containing lipoproteins, as well as with abnormal HDL composition.

  11. Inhibition of LDL oxidation and oxidized LDL-induced foam cell formation in RAW 264.7 cells show anti-atherogenic properties of a foliar methanol extract of Scoparia dulcis

    PubMed Central

    Nambiar, Sinjitha S.; Shetty, Nandini Prasad; Bhatt, Praveena; Neelwarne, Bhagyalakshmi

    2014-01-01

    Background: Oxidation of low density lipoproteins and their further uptake by macrophages is known to result in the formation of foam cells, which are critical in the initiation of atherosclerosis through activation of inflammatory signalling cascades. Thus, powerful dietary antioxidants are receiving attention for the reversal of such pathological states. Materials and Methods: Extracts of Scoparia dulcis have been used as tea and health drinks with various health promoting effects. In the present study, we examined the reactive oxygen scavenging potential as well as anti-inflammatory and anti-atherogenic efficacies, using leaf extracts obtained after successive extraction with various solvents. Results: A methanol extract showed potent antioxidant activity with an IC50 value of 570 μg/ml, caused hydrogen peroxide scavenging (28.9 µg/ml) and anti-inflammatory effects by improving human erythrocyte membrane stabilisation (about 86%). The methanol extract also efficiently inhibited lipid peroxidation and oxidation of low density lipoproteins, thus preventing foam cell formation in cultured RAW 264.7 cells. Furthermore, phytochemical screening of the extracts showed high accumulation of flavonoids. Conclusions: The foliar methanol extract of Scoparia dulcis has a strong anti-atherogenic potential and this property could be attributed maybe due to presence of flavonoids since HPLC analysis showed high concentrations of myricetin and rutin in the methanol extract. PMID:24991098

  12. Interplay between CRP, Atherogenic LDL, and LOX-1 and Its Potential Role in the Pathogenesis of Atherosclerosis.

    PubMed

    Stancel, Nicole; Chen, Chih-Chieh; Ke, Liang-Yin; Chu, Chih-Sheng; Lu, Jonathan; Sawamura, Tatsuya; Chen, Chu-Huang

    2016-02-01

    Studies have shown that the classic acute-phase protein C-reactive protein (CRP) has proinflammatory effects on vascular cells and may play a causal role in the pathogenesis of coronary artery disease. A growing body of evidence has suggested that interplay between CRP, lectin-like oxidized LDL receptor-1 (LOX-1), and atherogenic LDL may underlie the mechanism of endothelial dysfunction that leads to atherosclerosis. We review the biochemical evidence for an association of CRP, LOX-1, and either oxidized LDL (OxLDL) or electronegative L5 LDL with the pathogenesis of coronary artery disease. Artificially oxidized OxLDL has been studied extensively for its role in atherogenesis, as has electronegative L5 LDL, which is present at increased levels in patients with increased cardiovascular risks. OxLDL and L5 have been shown to stimulate human aortic endothelial cells to produce CRP, indicating that CRP is synthesized locally in the endothelium. The ligand-binding face (B-face) of CRP has been shown to bind the LOX-1 scavenger receptor and increase LOX-1 expression in endothelial cells, thereby promoting the uptake of OxLDL or L5 by LOX-1 into endothelial cells to induce endothelial dysfunction. CRP and LOX-1 may form a positive feedback loop with OxLDL or L5 in atherogenesis, whereby increased levels of atherogenic LDL in patients with cardiovascular risks induce endothelial cells to express CRP, which may in turn increase the expression of LOX-1 to promote the uptake of atherogenic LDL into endothelial cells. Further research is needed to confirm a causal role for CRP in atherogenesis. © 2015 American Association for Clinical Chemistry.

  13. Combined Effects of Curcumin and Lycopene or Bixin in Yoghurt on Inhibition of LDL Oxidation and Increases in HDL and Paraoxonase Levels in Streptozotocin-Diabetic Rats

    PubMed Central

    Assis, Renata Pires; Arcaro, Carlos Alberto; Gutierres, Vânia Ortega; Oliveira, Juliana Oriel; Costa, Paulo Inácio; Baviera, Amanda Martins; Brunetti, Iguatemy Lourenço

    2017-01-01

    Combination therapy using natural antioxidants to manage diabetes mellitus and its complications is an emerging trend. The aim of this study was to investigate the changes promoted by treatment of streptozotocin (STZ)-diabetic rats with yoghurt enriched with the bioactives curcumin, lycopene, or bixin (the latter two being carotenoids). Antioxidants were administered individually, or as mixtures, and biomarkers of metabolic and oxidative disturbances, particularly those associated with cardiovascular risk, were assessed. Treatment of STZ-diabetic rats with natural products individually decreased glycemia, triacylglycerol, total-cholesterol, oxidative stress biomarkers, including oxidized low-density lipoprotein (ox-LDL), and increased the activities of antioxidant enzymes. Individual carotenoids increased both high-density lipoprotein (HDL) and paraoxonase levels, whereas curcumin increased only paraoxonase. Treatments with mixtures of curcumin and lycopene or bixin had combined effects, decreasing biomarkers of carbohydrate and lipid disturbances (curcumin effect), increasing the HDL levels (carotenoids effects) and mitigating oxidative stress (curcumin and carotenoids effects). The combined effects also led to prevention of the LDL oxidation, thereby mitigating the cardiovascular risk in diabetes. These findings provide evidence for the beneficial effect of curcumin and carotenoid mixtures as a supplementation having antioxidant and antiatherogenic potentials, thus appearing as an interesting strategy to be studied as a complementary therapy for diabetic complications. PMID:28333071

  14. Combined Effects of Curcumin and Lycopene or Bixin in Yoghurt on Inhibition of LDL Oxidation and Increases in HDL and Paraoxonase Levels in Streptozotocin-Diabetic Rats.

    PubMed

    Assis, Renata Pires; Arcaro, Carlos Alberto; Gutierres, Vânia Ortega; Oliveira, Juliana Oriel; Costa, Paulo Inácio; Baviera, Amanda Martins; Brunetti, Iguatemy Lourenço

    2017-03-23

    Combination therapy using natural antioxidants to manage diabetes mellitus and its complications is an emerging trend. The aim of this study was to investigate the changes promoted by treatment of streptozotocin (STZ)-diabetic rats with yoghurt enriched with the bioactives curcumin, lycopene, or bixin (the latter two being carotenoids). Antioxidants were administered individually, or as mixtures, and biomarkers of metabolic and oxidative disturbances, particularly those associated with cardiovascular risk, were assessed. Treatment of STZ-diabetic rats with natural products individually decreased glycemia, triacylglycerol, total-cholesterol, oxidative stress biomarkers, including oxidized low-density lipoprotein (ox-LDL), and increased the activities of antioxidant enzymes. Individual carotenoids increased both high-density lipoprotein (HDL) and paraoxonase levels, whereas curcumin increased only paraoxonase. Treatments with mixtures of curcumin and lycopene or bixin had combined effects, decreasing biomarkers of carbohydrate and lipid disturbances (curcumin effect), increasing the HDL levels (carotenoids effects) and mitigating oxidative stress (curcumin and carotenoids effects). The combined effects also led to prevention of the LDL oxidation, thereby mitigating the cardiovascular risk in diabetes. These findings provide evidence for the beneficial effect of curcumin and carotenoid mixtures as a supplementation having antioxidant and antiatherogenic potentials, thus appearing as an interesting strategy to be studied as a complementary therapy for diabetic complications.

  15. Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor

    PubMed Central

    Chu, Chih-Sheng; Wang, Yu-Chen; Lu, Long-Sheng; Walton, Brian; Yilmaz, H. Ramazan; Huang, Roger Y.; Sawamura, Tatsuya; Dixon, Richard A. F.; Lai, Wen-Ter; Chen, Chu-Huang; Lu, Jonathan

    2013-01-01

    Objectives Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1. Methods and Results Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5]  =  L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine. Conclusions Our results suggest that CRP, L5, and LOX-1 form a cyclic

  16. Plasma instabilities in electronegative inductive discharges

    NASA Astrophysics Data System (ADS)

    Marakhtanov, Alexei Mikhail

    Plasma instabilities have been observed in low-pressure inductive discharges, in the transition between low density capacitive mode and high density inductive mode of the discharge when attaching gases such as SF6 and Ar/SF 6 mixtures are used. Oscillations of charged particles, plasma potential and light emitted from the plasma with the frequencies from a few hertz to tens of kilohertz are seen for gas pressures between 1 and 100 mTorr and the discharge power in the range of 75--1200 W. The region of instability increases as the plasma becomes more electronegative and the frequency of plasma oscillations increases as the power, pressure, and gas flow rate increase. The instability frequencies may also depend on the settings of a matching network. A volume-averaged (global) model of the instability has been developed, for a discharge containing time varying densities of electrons, positive ions, and negative ions, and time invariant excited states and neutral densities. The particle and energy balance equations are integrated to produce the dynamical behavior. As pressure or power is varied to cross a threshold, the instability goes through a series of oscillatory states to large scale relaxation oscillations between higher and lower density states. The model qualitatively agrees with experimental observations, and also shows a significant influence of the matching network. A stability analysis of an electronegative discharge has been performed, using a Hurwitz criterion, for a system of linearized particle and power balance differential equations. Capacitive coupling plays a crucial role in the instability process. A variable electrostatic (Faraday) shield has been used to control the capacitive coupling from the excitation coil to the plasma. The plasma instability disappears when the shielded area exceeds 65% of the total area of the coil. The global model of instability gives a slightly higher value of 85% for instability suppression with the same discharge

  17. Electronegative low density lipoprotein induces renal apoptosis and fibrosis: STRA6 signaling involved[S

    PubMed Central

    Chen, Chao-Hung; Ke, Liang-Yin; Chan, Hua-Chen; Lee, An-Sheng; Lin, Kun-Der; Chu, Chih-Sheng; Lee, Mei-Yueh; Hsiao, Pi-Jung; Hsu, Chin; Chen, Chu-Huang; Shin, Shyi-Jang

    2016-01-01

    Dyslipidemia has been proven to capably develop and aggravate chronic kidney disease. We also report that electronegative LDL (L5) is the most atherogenic LDL. On the other hand, retinoic acid (RA) and RA receptor (RAR) agonist are reported to be beneficial in some kidney diseases. “Stimulated by retinoic acid 6” (STRA6), one retinol-binding protein 4 receptor, was recently identified to regulate retinoid homeostasis. Here, we observed that L5 suppressed STRA6 cascades [STRA6, cellular retinol-binding protein 1 (CRBP1), RARs, retinoid X receptor α, and retinol, RA], but L5 simultaneously induced apoptosis and fibrosis (TGFβ1, Smad2, collagen 1, hydroxyproline, and trichrome) in kidneys of L5-injected mice and L5-treated renal tubular cells. These L5-induced changes of STRA6 cascades, renal apoptosis, and fibrosis were reversed in kidneys of LOX1−/− mice. LOX1 RNA silencing and inhibitor of c-Jun N-terminal kinase and p38MAPK rescued the suppression of STRA6 cascades and apoptosis and fibrosis in L5-treated renal tubular cells. Furthermore, crbp1 gene transfection reversed downregulation of STRA6 cascades, apoptosis, and fibrosis in L5-treated renal tubular cells. For mimicking STRA6 deficiency, efficient silencing of STRA6 RNA was performed and was found to repress STRA6 cascades and caused apoptosis and fibrosis in L1-treated renal tubular cells. In summary, this study reveals that electronegative L5 can cause kidney apoptosis and fibrosis via the suppression of STRA6 cascades, and implicates that STRA6 signaling may be involved in dyslipidemia-mediated kidney disease. PMID:27256691

  18. Electronegativity determination of individual surface atoms by atomic force microscopy

    NASA Astrophysics Data System (ADS)

    Onoda, Jo; Ondráček, Martin; Jelínek, Pavel; Sugimoto, Yoshiaki

    2017-04-01

    Electronegativity is a fundamental concept in chemistry. Despite its importance, the experimental determination has been limited only to ensemble-averaged techniques. Here, we report a methodology to evaluate the electronegativity of individual surface atoms by atomic force microscopy. By measuring bond energies on the surface atoms using different tips, we find characteristic linear relations between the bond energies of different chemical species. We show that the linear relation can be rationalized by Pauling's equation for polar covalent bonds. This opens the possibility to characterize the electronegativity of individual surface atoms. Moreover, we demonstrate that the method is sensitive to variation of the electronegativity of given atomic species on a surface due to different chemical environments. Our findings open up ways of analysing surface chemical reactivity at the atomic scale.

  19. Electronegativity determination of individual surface atoms by atomic force microscopy

    PubMed Central

    Onoda, Jo; Ondráček, Martin; Jelínek, Pavel; Sugimoto, Yoshiaki

    2017-01-01

    Electronegativity is a fundamental concept in chemistry. Despite its importance, the experimental determination has been limited only to ensemble-averaged techniques. Here, we report a methodology to evaluate the electronegativity of individual surface atoms by atomic force microscopy. By measuring bond energies on the surface atoms using different tips, we find characteristic linear relations between the bond energies of different chemical species. We show that the linear relation can be rationalized by Pauling's equation for polar covalent bonds. This opens the possibility to characterize the electronegativity of individual surface atoms. Moreover, we demonstrate that the method is sensitive to variation of the electronegativity of given atomic species on a surface due to different chemical environments. Our findings open up ways of analysing surface chemical reactivity at the atomic scale. PMID:28443645

  20. Electronegativity determination of individual surface atoms by atomic force microscopy.

    PubMed

    Onoda, Jo; Ondráček, Martin; Jelínek, Pavel; Sugimoto, Yoshiaki

    2017-04-26

    Electronegativity is a fundamental concept in chemistry. Despite its importance, the experimental determination has been limited only to ensemble-averaged techniques. Here, we report a methodology to evaluate the electronegativity of individual surface atoms by atomic force microscopy. By measuring bond energies on the surface atoms using different tips, we find characteristic linear relations between the bond energies of different chemical species. We show that the linear relation can be rationalized by Pauling's equation for polar covalent bonds. This opens the possibility to characterize the electronegativity of individual surface atoms. Moreover, we demonstrate that the method is sensitive to variation of the electronegativity of given atomic species on a surface due to different chemical environments. Our findings open up ways of analysing surface chemical reactivity at the atomic scale.

  1. Electronegative plasma equilibria with spatially varying ionization

    NASA Astrophysics Data System (ADS)

    Kawamura, E.; Lichtenberg, A. J.; Lieberman, M. A.

    2012-12-01

    Electronegative inductive discharges in higher pressure ranges typically exhibit strongly localized ionization near the coil structure, with decay of the electron temperature and ionization into the central discharge region. We use a two-dimensional (2D) fluid code with a chlorine feedstock gas to determine the spatial profiles of the particle densities and electron temperature in a cylindrical transformer-coupled plasma device excited by a stove-top coil on top of the plasma chamber. To compare with one-dimensional (1D) analytical models, the 2D results are area-averaged over the radius. The area-averaged ionization frequency νiz is found to decay exponentially away from the coils, allowing the ansatz of an exponentially decaying axial variation for νiz to be used in a 1D numerical model. The 1D model captures the main features of the axial variations of the area-averaged 2D fluid simulation, indicating that the main diffusion mechanisms act along the axial direction. A simple analytical global discharge model is also developed, accounting for the asymmetric density and ionization profiles. The global model gives the scalings of the ion densities and electron temperature with power and pressure. The 1D and global models are compared with the 2D fluid simulations, showing reasonable agreement.

  2. Electronegative Plasma Instabilities in Industrial Pulsed Plasmas

    NASA Astrophysics Data System (ADS)

    Pribyl, Patrick; Hansen, Anders; Gekelman, Walter

    2016-10-01

    Electronegative gases that are important for industrial etch processes have a series of instabilities that occur at process relevant conditions. These have been studied since the 1990s, but are becoming a much more important today as plasma reactors are being pushed to produce ever finer features, and tight control of the etch process is becoming crucial. The experiments are being done in a plasma etch tool that closely simulates a working industrial device. ICP coils in different configurations are driven by a pulsed RF generators operating at 2-5 MHz. A computer controlled automated probe drive can access a volume above the substrate. The probe can be a Langmuir probe, a ``Bdot'' probe, or an emissive probe the latter used for more accurate determination of plasma potential. A microwave interferometer is available to measure line-averaged electron density. The negative ion instability is triggered depending upon the gas mix (Ar,SF6) , pressure and RF power. The instability can be ``burned through'' by rapidly pulsing the RF power. In this study we present measurements of plasma current and density distribution over the wafer before, after and during the rapid onset of the instability. Work suported by NSF-GOALI Award and done at the BAPSF.

  3. Four Statin Benefit Groups Defined by The 2013 ACC/AHA New Cholesterol Guideline are Characterized by Increased Plasma Level of Electronegative Low-Density Lipoprotein

    PubMed Central

    Chu, Chih-Sheng; Ke, Liang-Yin; Chan, Hua-Chen; Chan, Hsiu-Chua; Chen, Chih-Chieh; Cheng, Kai-Hung; Lee, Hsiang-Chun; Kuo, Hsuan-Fu; Chang, Ching-Tang; Chang, Kuan-Cheng; Sheu, Sheng-Hsiung; Chen, Chu-Huang; Lai, Wen-Ter

    2016-01-01

    Background Significantly higher cytotoxic and thrombogenic human electronegative low-density lipoprotein (LDL), or L5, has been found in patients with stable coronary artery disease and acute coronary syndrome. We hypothesized that the statin-benefit groups (SBGs) defined by the new cholesterol guideline were of higher electronegative L5. Methods In total, 62 hyperlipidemia patients (mean age 59.4 ± 10.5, M/F 40/22) were retrospectively divided into SBGs (n = 44) and N-SBGs (n = 18). The levels of complete basic lipid panel, biochemical profile and electronegative L5 of each individual were obtained before and after rosuvastatin 10 mg/day for 3 months. Results After 3 months’ statin therapy, significant reduction of total cholesterol, LDL-C and triglyceride were demonstrated (all p-values < 0.05), with 38.4% LDL-C reduction. The percentage of L5 was significantly reduced by 40.9% (from 4.4% to 2.6%) after statin therapy (p = 0.001). Regarding absolute L5 concentration, derived from L5% multiplied by LDL-C, there was approximate 63.8% reduction (from 6.3 mg/dL to 2.3 mg/dL) of absolute L5 (p < 0.001) after statin treatment. Notably, while plasma LDL-C levels were similar between SBGs and N-SBGs (152.8 ± 48.6 vs. 146.9 ± 35.0 mg/dL), the SBGs had significantly elevated L5% (5.2 ± 7.4% vs. 2.6 ± 1.9%, p = 0.031) and higher absolute L5 concentration (7.4 ± 10.4 vs. 3.7 ± 3.1 mg/dL, p = 0.036). Linear regression showed the significantly positive correlation between the plasma L5 concentration and the 10-year cardiovascular risk by pooled cohort equation (r = 0.297, p < 0.05). Conclusions The four SBGs defined by the 2013 ACC/AHA new cholesterol guideline tend to have increased atherogenic electronegative L5. Statin therapy can effectively reduce the electronegative L5 of these four major SBGs. PMID:27899853

  4. Effect of improving glycemic control in patients with type 2 diabetes mellitus on low-density lipoprotein size, electronegative low-density lipoprotein and lipoprotein-associated phospholipase A2 distribution.

    PubMed

    Sánchez-Quesada, José L; Vinagre, Irene; de Juan-Franco, Elena; Sánchez-Hernández, Juan; Blanco-Vaca, Francisco; Ordóñez-Llanos, Jordi; Pérez, Antonio

    2012-07-01

    The aim of this study was to determine the effect of intensified hypoglycemic therapy in patients with type 2 diabetes mellitus on the distribution of lipoprotein-associated phospholipase A2 (Lp-PLA2) activity between high-density lipoprotein and low-density lipoprotein (LDL) and its relation with the lipid profile and other qualitative properties of LDL. Forty-two patients with type 2 diabetes on the basis of poor glycemic control and normal or near normal LDL cholesterol were recruited. Lifestyle counseling and pharmacologic hypoglycemic therapy were intensified to improve glycemic control, but lipid-lowering therapy was unchanged. At 4 ± 2 months, glycosylated hemoglobin had decreased by a mean of 2.1%, but the only effect on the lipid profile were statistically significant decreases in nonesterified fatty acids and apolipoprotein B concentration. LDL size increased and the proportion of electronegative LDL decreased significantly. In parallel, total Lp-PLA2 activity decreased significantly, promoting a redistribution of Lp-PLA2 activity toward a higher proportion in high-density lipoprotein. Improvements in glycemic control led to more marked changes in Lp-PLA2 activity and distribution in patients with diabetes who had not received previous lipid-lowering therapy. In conclusion, optimizing glycemic control in patients with type 2 diabetes promotes atheroprotective changes, including larger LDL size, decreased electronegative LDL, and a higher proportion of Lp-PLA2 activity in high-density lipoprotein.

  5. [The LDL receptor family].

    PubMed

    Meilinger, Melinda

    2002-12-29

    The members of the LDL receptor family are structurally related endocytic receptors. Our view on these receptors has considerably changed in recent years. Not only have new members of the family been identified, but also several interesting observations have been published concerning the biological function of these molecules. The LDL receptor family members are able to bind and internalize a plethora of ligands; as a consequence, they play important roles in diverse physiological processes. These receptors are key players in the lipoprotein metabolism, vitamin homeostasis, Ca2+ homeostasis, cell migration, and embryonic development. Until recently, LDL receptor family members were thought to be classic endocytic receptors that provide cells with metabolites on one hand, while regulating the concentration of their ligands in the extracellular fluids on the other hand. However, recent findings indicate that in addition to their cargo transport function, LDL receptor family members can act as signal transducers, playing important roles in the development of the central nervous system or the skeleton. Better understanding of physiological and pathophysiological functions of these molecules may open new avenues for the treatment or prevention of many disorders.

  6. Protective effects of berberine against low-density lipoprotein (LDL) oxidation and oxidized LDL-induced cytotoxicity on endothelial cells.

    PubMed

    Hsieh, Yih-Shou; Kuo, Wu-Hsien; Lin, Ta-Wei; Chang, Horng-Rong; Lin, Teseng-His; Chen, Pei-Ni; Chu, Shu-Chen

    2007-12-12

    The oxidative modification of low-density lipoprotein (LDL) is thought to have a central role in the pathogenesis of atherogenesis. Berberine, a natural constituent of plants of the genera Coptis and Berberis, has several anti-inflammation and anticancer biological effects. However, its protective effects on LDL oxidation and endothelial injury induced by oxLDL remain unclear. In this study, we evaluated the antioxidative activity of berberine and how berberine rescues human umbilical vein endothelial cells (HUVECs) from oxidized LDL (oxLDL)-mediated dysfunction. The antioxidative activity of berberine was defined by the relative electrophoretic mobility of oxLDL, fragmentation of ApoB, and malondialdehyde production via the Cu(2+)-mediated oxidation of LDL. Berberine also inhibited the generation of ROS and the subsequent mitochondrial membrane potential collapse, chromosome condensation, cytochrome C release, and caspase-3 activation induced by oxLDL in HUVECs. Our results suggest that berberine may protect LDL oxidation and prevent oxLDL-induced cellular dysfunction.

  7. A novel alkaloid antioxidant, Boldine and synthetic antioxidant, reduced form of RU486, inhibit the oxidation of LDL in-vitro and atherosclerosis in vivo in LDLR(-/-) mice.

    PubMed

    Santanam, N; Penumetcha, M; Speisky, H; Parthasarathy, S

    2004-04-01

    A corollary to the oxidation hypothesis of atherosclerosis is that the consumption of antioxidants is beneficial. However, the literature is divided in support of this conclusion. In this study, Boldine, an alkaloid of Peumus boldus and reduced form of RU486, was tested for their antioxidant potency both in, in vitro oxidation system and in mouse models. Boldine decreased the ex-vivo oxidation of low-density lipoprotein (LDL). Two different in vivo studies were performed to study the effect of these compounds on the atherosclerotic lesion formation in LDLR(-/-) mice. In study I, three groups of LDLR(-/-) mice (N = 12 each) were fed an atherogenic diet. Group 1 was given vehicle and group 2 and 3 were given 1mg of Boldine or Red RU per day for 12 weeks. In study II, two groups of LDLR(-/-) mice N = 10 each) were fed an atherogenic diet. Group 1 was given vehicle and group 2 was given 5mg of Boldine per day. The results indicated that there was a decrease in lesion formation reaching a 40% reduction due to Boldine and 45% reduction by Red RU compared to controls. The in vivo tolerance of Boldine in humans (has been used as an herbal medicine in other diseases) should make it an attractive alternative to Vitamin E.

  8. The Effect of a Shear Flow on the Uptake of LDL and Ac-LDL by Cultured Vascular Endothelial Cells

    NASA Astrophysics Data System (ADS)

    Niwa, Koichi; Karino, Takeshi

    The effects of a shear flow on the uptake of fluorescence-labeled low-density lipoprotein (DiI-LDL), acetylated LDL (DiI-Ac-LDL), and lucifer yellow (LY; a tracer of fluid-phase endocytosis) by cultured bovine aortic ECs were studied using a rotating-disk shearing apparatus. It was found that 2hours’ exposure of ECs to a laminar shear flow that imposed ECs an area-mean shear stress of 10dynes/cm2 caused an increase in the uptake of DiI-LDL and LY. By contrast, the uptake of DiI-Ac-LDL was decreased by exposure of the ECs to a shear flow. Addition of dextran sulfate (DS), a competitive inhibitor of scavenger receptors, reversed the effect of a shear flow on the uptake of DiI-Ac-LDL, resulting in an increase by the imposition of a shear flow, while the uptake of DiI-LDL and LY remained unaffected. It was concluded that a shear flow promotes the endocytosis of DiI-LDL and LY by ECs, but suppresses the uptake of DiI-Ac-LDL by ECs by inhibiting scavenger receptor-mediated endocytosis.

  9. Electronegative Guests in CoSb3

    SciTech Connect

    Duan, Bo; Yang, Jiong; Salvador, James R.; He, Yang; Zhao, Bo; Wang, Shanyu; Wei, Ping; Ohuchi, Fumio; Zhang, Wenqing; Hermann, Raphael P.; Gourdon, Olivier; Mao, Scott; Cheng, Yingwen; Wang, Chongmin; Liu, Jun; Zhai, Pengcheng; Tang, Xinfeng; Zhang, Qingjie; Yang, Jihui

    2016-04-19

    Introducing guests into a host framework to form a so called inclusion compound can be used to design materials with new and fascinating functionalities. The vast majority of inclusion compounds have electropositive guests with neutral or negatively charged frameworks. Here, we show a series of electronegative guest filled skutterudites with inverse polarity. The strong covalent guest-host interactions observed for the electronegative group VIA guests, i.e., S and Se, feature a unique localized cluster vibration which significantly influences the lattice dynamics, together with the point-defect scattering caused by element substitutions, resulting in very low lattice thermal conductivity values. The findings of electronegative guests provide a new perspective for guest-filling in skutterudites, and the covalent filler/lattice interactions lead to an unusual lattice dynamics phenomenon which can be used for designing high-efficiency thermoelectric materials and novel functional inclusion compounds with open structures.

  10. Electronegative Guests in CoSb3

    SciTech Connect

    Duan, Bo; Yang, Jiong; Salvador, James R.; He, Yang; Zhao, Bo; Wang, Shanyu; Wei, Ping; Ohuchi, Fumio; Zhang, Wenqing; Hermann, Raphael P.; Gourdon, Olivier; Mao, Scott; Cheng, Yingwen; Wang, Chongmin; Liu, Jun; Zhai, Pengcheng; Tang, Xinfeng; Zhang, Qingjie; Yang, Jihui

    2016-04-19

    Introducing guests into a host framework to form a so called inclusion compound can be used to design materials with new and fascinating functionalities. The vast majority of inclusion compounds have electropositive guests with neutral or negatively charged frameworks. Here, we show a series of electronegative guest filled skutterudites with inverse polarity. The strong covalent guest-host interactions observed for the electronegative group VIA guests, i.e., S and Se, feature a unique localized cluster vibration which significantly influences the lattice dynamics, together with the point-defect scattering caused by element substitutions, resulting in very low lattice thermal conductivity values. The findings of electronegative guests provide a new perspective for guest-filling in skutterudites, and the covalent filler/lattice interactions lead to an unusual lattice dynamics phenomenon which can be used for designing high-efficiency thermoelectric materials and novel functional inclusion compounds with open structures.

  11. [LDL-apheresis: current status].

    PubMed

    Stefanutti, C; Vivenzio, A; Lucani, G; Di Giacomo, S

    2001-01-01

    State of the art of LDL-apheresis and treatment of severe familiar hypercholesterolemia. Clinical experience of treatment with LDL-apheresis of pediatric and adult patients with familial hypercholesterolemia using the following techniques: D.A.L.I., H.E.L.P., D.S.C. The outcome of treatment with LDL-apheresis in young patients, using the most recently introduced techniques, is reported. We have submitted to LDL-apheresis 11 pediatric patients. The youngest is aged 3.5. LDL-apheresis is able at improving the metabolic impairment and halting the natural evolution of atherosclerotic disease and atherosclerotic complications. At present, LDL-apheresis is the most effective and safe therapeutic approach to the treatment of homozygous, heterozygous and double heterozygous familial hypercholesterolemia.

  12. Design and Preliminary Testing Plan of Electronegative Ion Thruster

    NASA Technical Reports Server (NTRS)

    Schloeder, Natalie R.; Liu, Thomas M.; Walker, Mitchell L. R.; Polzin, Kurt A.; Dankanich, John W.; Aanesland, Ane

    2014-01-01

    Electronegative ion thrusters are a new iteration of existing gridded ion thruster technology differentiated by their ability to produce and accelerate both positive and negative ions. The primary motivations for electronegative ion thruster development include the elimination of lifetime-limiting cathodes from a thruster system and the ability to generate appreciable thrust through the acceleration of both positive or negative-charged ions. Proof-of-concept testing of the PEGASES (Plasma Propulsion with Electronegative GASES) thruster demonstrated the production of positively and negatively-charged ions (argon and sulfur hexafluoride, respectively) in an RF discharge and the subsequent acceleration of each charge species through the application of a time-varying electric field to a pair of metallic grids similar to those found in gridded ion thrusters. Leveraging the knowledge gained through experiments with the PEGASES I and II prototypes, the MINT (Marshall's Ion-ioN Thruster) is being developed to provide a platform for additional electronegative thruster proof-of-concept validation testing including direct thrust measurements. The design criteria used in designing the MINT are outlined and the planned tests that will be used to characterize the performance of the prototype are described.

  13. Apolipoprotein A-I mimetic peptide 4F blocks sphingomyelinase-induced LDL aggregation.

    PubMed

    Nguyen, Su Duy; Javanainen, Matti; Rissanen, Sami; Zhao, Hongxia; Huusko, Jenni; Kivelä, Annukka M; Ylä-Herttuala, Seppo; Navab, Mohamad; Fogelman, Alan M; Vattulainen, Ilpo; Kovanen, Petri T; Öörni, Katariina

    2015-06-01

    Lipolytic modification of LDL particles by SMase generates LDL aggregates with a strong affinity for human arterial proteoglycans and may so enhance LDL retention in the arterial wall. Here, we evaluated the effects of apoA-I mimetic peptide 4F on structural and functional properties of the SMase-modified LDL particles. LDL particles with and without 4F were incubated with SMase, after which their aggregation, structure, and proteoglycan binding were analyzed. At a molar ratio of L-4F to apoB-100 of 2.5 to 20:1, 4F dose-dependently inhibited SMase-induced LDL aggregation. At a molar ratio of 20:1, SMase-induced aggregation was fully blocked. Binding of 4F to LDL particles inhibited SMase-induced hydrolysis of LDL by 10% and prevented SMase-induced LDL aggregation. In addition, the binding of the SMase-modified LDL particles to human aortic proteoglycans was dose-dependently inhibited by pretreating LDL with 4F. The 4F stabilized apoB-100 conformation and inhibited SMase-induced conformational changes of apoB-100. Molecular dynamic simulations showed that upon binding to protein-free LDL surface, 4F locally alters membrane order and fluidity and induces structural changes to the lipid layer. Collectively, 4F stabilizes LDL particles by preventing the SMase-induced conformational changes in apoB-100 and so blocks SMase-induced LDL aggregation and the resulting increase in LDL retention. Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.

  14. LDL oxidation by platelets propagates platelet activation via an oxidative stress-mediated mechanism.

    PubMed

    Carnevale, Roberto; Bartimoccia, Simona; Nocella, Cristina; Di Santo, Serena; Loffredo, Lorenzo; Illuminati, Giulio; Lombardi, Elisabetta; Boz, Valentina; Del Ben, Maria; De Marco, Luigi; Pignatelli, Pasquale; Violi, Francesco

    2014-11-01

    Platelets generate oxidized LDL (ox-LDL) via NOX2-derived oxidative stress. We investigated if once generated by activated platelets ox-LDL can propagate platelet activation. Experiments were performed in platelets from healthy subjects (HS), hyper-cholesterolemic patients and patients with NOX2 hereditary deficiency. Agonist-stimulated platelets from HS added with LDL were associated with a dose-dependent increase of reactive oxidant species and ox-LDL. Agonist-stimulated platelets from HS added with a fixed dose of LDL (57.14 μmol/L) or added with homogenized human atherosclerotic plaque showed enhanced ox-LDL formation (approximately +50% and +30% respectively), which was lowered by a NOX2 inhibitor (approximately -35% and -25% respectively). Compared to HS, ox-LDL production was more pronounced in agonist-stimulated platelet rich plasma (PRP) from hyper-cholesterolemic patients but was almost absent in PRP from NOX2-deficient patients. Platelet aggregation and 8-iso-PGF2α-ΙΙΙ formation increased in LDL-treated washed platelets (+42% and +53% respectively) and PRP (+31% and +53% respectively). Also, LDL enhanced platelet-dependent thrombosis at arterial shear rate (+33%) but did not affect platelet activation in NOX2-deficient patients. Platelet activation by LDL was significantly inhibited by CD36 or LOX1 blocking peptides, two ox-LDL receptor antagonists, or by a NOX2 inhibitor. LDL-added platelets showed increased p38MAPK (+59%) and PKC (+51%) phosphorylation, p47(phox) translocation to platelet membrane (+34%) and NOX2 activation (+30%), which were inhibited by ox-LDL receptor antagonists. Platelets oxidize LDL, which in turn amplify platelet activation via specific ox-LDL receptors; both effects are mediated by NOX2 activation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Genistein, the dietary-derived angiogenesis inhibitor, prevents LDL oxidation and protects endothelial cells from damage by atherogenic LDL.

    PubMed

    Kapiotis, S; Hermann, M; Held, I; Seelos, C; Ehringer, H; Gmeiner, B M

    1997-11-01

    There is now growing evidence that the oxidative modification of LDL plays a potential role in atherosclerosis. In this study, genistein, a compound derived from a soy diet with a flavonoid chemical structure (4',5,7-trihydroxyisoflavone), which was found to inhibit angiogenesis, has been evaluated for its ability to act as an LDL antioxidant and a vascular cell protective agent against oxidized LDL. The results showed that genistein was able to inhibit the oxidation of LDL in the presence of copper ions or superoxide/nitric oxide radicals as measured by thiobarbituric acid-reactive substance formation, alteration in electrophoretic mobility, and lipid hydroperoxides. Bovine aortic endothelial cell- and human endothelial cell-mediated LDL oxidation was also inhibited in the presence of genistein. The 7-O-glucoside of genistein, genistin, was much less effective in inhibiting LDL oxidation in the cell-free and cell-mediated lipoprotein-oxidating systems. Incubating human endothelial cells in the absence or presence of genistein and challenging the cells with already oxidized lipoprotein revealed that in addition to its antioxidative potential during LDL oxidating processes, genistein effectively protected the vascular cells from damage by oxidized lipoproteins. The tyrosine kinase inhibitor genistein was found to block upregulation of two tyrosine-phosphorylated proteins of 132 and 69 kDa in endothelial cells induced by oxidized LDL. Parallel experiments with the inactive analogue daidzein, however, showed that the cytoprotective effect of the isoflavones seems not to be dependent on tyrosine phosphorylation. Our findings will support the suggested and documented beneficial action of a soy diet in preventing chronic vascular diseases and early atherogenic events.

  16. Design and Preliminary Performance Testing of Electronegative Gas Plasma Thruster

    NASA Technical Reports Server (NTRS)

    Liu, Thomas M.; Schloeder, Natalie R.; Walker, Mitchell L. R.; Polzin, Kurt A.; Dankanich, John W.; Aanesland, Ane

    2014-01-01

    In classical gridded electrostatic ion thrusters, positively charged ions are generated from a plasma discharge of noble gas propellant and accelerated to provide thrust. To maintain overall charge balance on the propulsion system, a separate electron source is required to neutralize the ion beam as it exits the thruster. However, if high-electronegativity propellant gases (e.g., sulfur hexafluoride) are instead used, a plasma discharge can result consisting of both positively and negatively charged ions. Extracting such electronegative plasma species for thrust generation (e.g., with time-varying, bipolar ion optics) would eliminate the need for a separate neutralizer cathode subsystem. In addition for thrusters utilizing a RF plasma discharge, further simplification of the ion thruster power system may be possible by also using the RF power supply to bias the ion optics. Recently, the PEGASES (Plasma propulsion with Electronegative gases) thruster prototype successfully demonstrated proof-of-concept operations in alternatively accelerating positively and negatively charged ions from a RF discharge of a mixture of argon and sulfur hexafluoride.i In collaboration with NASA Marshall Space Flight Center (MSFC), the Georgia Institute of Technology High-Power Electric Propulsion Laboratory (HPEPL) is applying the lessons learned from PEGASES design and testing to develop a new thruster prototype. This prototype will incorporate design improvements and undergo gridless operational testing and diagnostics checkout at HPEPL in April 2014. Performance mapping with ion optics will be conducted at NASA MSFC starting in May 2014. The proposed paper discusses the design and preliminary performance testing of this electronegative gas plasma thruster prototype.

  17. Dynamics of electronegative plasmas for materials processing. Final report

    SciTech Connect

    Lichtenberg, A.J.; Lieberman, M.A.

    1996-12-31

    Purpose was to study equilibrium particle and energy balance and heating mechanisms in electronegative rf discharges. Attention is given to formation of non-Maxwellian electron distributions and their effect on macroscopic parameters. Research includes theory, particle- in-cell simulation, and experimental investigations. Sheath heating theory and simulation results for electropositive plasmas are used as guide. The investigation was centered on, but not limited to, study of oxygen feedstock gas in capacitively and inductively coupled rf discharges.

  18. Synthetic LDL as targeted drug delivery vehicle

    DOEpatents

    Forte, Trudy M [Berkeley, CA; Nikanjam, Mina [Richmond, CA

    2012-08-28

    The present invention provides a synthetic LDL nanoparticle comprising a lipid moiety and a synthetic chimeric peptide so as to be capable of binding the LDL receptor. The synthetic LDL nanoparticle of the present invention is capable of incorporating and targeting therapeutics to cells expressing the LDL receptor for diseases associated with the expression of the LDL receptor such as central nervous system diseases. The invention further provides methods of using such synthetic LDL nanoparticles.

  19. Mode transitions and electronegativity in oxygen CCP and ICP

    NASA Astrophysics Data System (ADS)

    Meichsner, Juergen; Wegner, Thomas

    2016-09-01

    Mode transitions in 13.56 MHz oxygen radio frequency plasmas (CCP, ICP) and their impact on the electron heating mechanisms and electronegativity were studied by advanced plasma diagnostics. In particular, Langmuir probe measurements, Gaussian beam microwave interferometry (160 GHz) coupled with laser photodetachment of negative oxygen ions, as well as the (phase resolved) optical emission and VUV absorption spectroscopy, and ion mass spectrometry are taken into consideration. With increasing RF power a transition between high and low electronegativity was found both in CCP and ICP discharge configuration. Thereby, the changed electron heating mechanisms, e.g., the alpha-gamma mode transition in CCP and the E-H mode transition in ICP is combined with the change of electronegativity. In strongly asymmetric CCP at moderate pressure the emission of secondary negative ions at the powered electrode have to be considered, too. Thereby, pseudo secondary electrons may be produced due to collision detachment of negative ion by metastables. During the E-H mode transition in oxygen ICP, the increasing gas temperature and the metastables influences significantly the oxygen kinetics. Supported by the DFG Collaborative Research Centre Transregio 24 ``Fundamentals of Complex Plasmas''.

  20. Reduction of copper, but not iron, by human low density lipoprotein (LDL). Implications for metal ion-dependent oxidative modification of LDL.

    PubMed

    Lynch, S M; Frei, B

    1995-03-10

    Cell-mediated oxidative modification of human low density lipoprotein (LDL), most likely an important early step in atherosclerosis, requires redox active metal ions such as copper or iron. We have previously shown that iron-dependent, in contrast to copper-dependent, oxidative modification of LDL requires superoxide, a physiological reductant. In the present study, we sought to explain these discrepant results. LDL was incubated at 37 degrees C with Cu2+ (10 microM) and bathocuproine (BC, 360 microM), an indicator molecule which specifically complexes Cu+, but not Cu2+. In a time- and concentration-dependent manner, LDL reduced Cu2+ to Cu+. An LDL concentration as low as 10 micrograms of protein/ml (about 20 nM) reduced about 7 microM Cu2+ within 1 h of incubation. Complexation of the Cu+ formed under these conditions with BC significantly inhibited oxidative modification of LDL, as assessed by agarose gel electrophoresis. Preincubation of LDL with N-ethylmaleimide had no effect on the rate and extent of Cu2+ reduction nor LDL oxidation, indicating that free sulfhydryl groups associated with apolipoprotein B are not involved. Addition of either superoxide dismutase or catalase or increasing the alpha-tocopherol content of LDL from 11.8 +/- 3.0 to 24.4 +/- 2.8 nmol/mg of protein also had no significant effect on the kinetics of Cu2+ reduction by LDL. In contrast, incubation of LDL with Fe(3+)-citrate (10 microM) and the indicator bathophenanthroline (BP, 360 microM) resulted in no significant Fe2+ formation, even at LDL concentrations as high as 200 micrograms of protein/ml. However, incubation of LDL with Fe(3+)-citrate and an enzymatic source of superoxide led to rapid formation of Fe2+ and consequent oxidative modification of LDL. Addition of BP inhibited iron-mediated LDL oxidation under these conditions. Our results indicate that reduced metal ions are important mediators of LDL oxidation, and that LDL specifically reduces Cu2+, but not Fe3+. These data

  1. Profound influence of LDL oxidative status and monocyte co-cultures on baboon endothelial activation

    PubMed Central

    Xiao, Juan; Hondara, Vida; Wang, Xing Li; VandeBerg, John L; Shi, Qiang

    2012-01-01

    Objective To investigate how increased LDL levels interact with endothelial cells by using well-defined LDL preparations to limit experimental biases caused by heterogeneity of LDL preparations. Methods We pooled LDL from multiple subjects and prepared several types of LDL from a single source. Then we observed their effects on cultured endothelial cells with and without monocyte co-culture. Results Native and minimally oxidized LDL did not cause significant cell death under most circumstances, and did not up-regulate cellular adhesion molecule (CAM) expression. Native LDL did result in significant increases of MCP-1 release in five of eight subjects. However, extensively oxidized LDL caused a significant amount of cell death and dramatically decreased MCP-1 secretion. Minimally oxidized LDL elicited a mixed response pattern, with a great deal of variation among subjects. When endothelial cells were co-cultured with monocytes and treated with native LDL, significant up-regulation of CAMs was detected after 24 hours of exposure. Up-regulation was not seen in any treatment group that contained either native LDL or monocytes only, indicating a synergistic effect of LDL and monocytes on endothelial cells. Incubation of cultured monocytes with native LDL also resulted in TNF-α and IL-1β release in a dosage- and time-dependent manner. Neutralization of both TNF-α and IL-1β by 10 μg/mL polyclonal antibodies inhibited the up-regulation of CAMs. Conclusion Our results suggest that varying extents of oxidative modification of LDL lead to fundamentally different cytological effects and that native LDL exhibits greater endothelial activation capacity when it interactively cooperates with monocytes. PMID:22254208

  2. Indium-111-labeled LDL: A potential agent for imaging atherosclerotic disease and lipoprotein biodistribution

    SciTech Connect

    Rosen, J.M.; Butler, S.P.; Meinken, G.E.; Wang, T.S.; Ramakrishnan, R.; Srivastava, S.C.; Alderson, P.O.; Ginsberg, H.N. )

    1990-03-01

    Radiolabeling of low-density lipoprotein (LDL) and external imaging with a gamma camera would offer a means of taking advantage of the metabolic activity of developing atherosclerotic lesions in order to noninvasively detect and determine the extent of atherosclerotic cardiovascular disease. Indium-111-({sup 111}In) labeled LDL was prepared and its purity demonstrated by agarose electrophoresis and ultracentrifugation. In vitro studies with cultured human fibroblasts demonstrated significant inhibition of iodine-125-({sup 125}I) LDL binding to LDL receptors by {sup 111}In-LDL, although this was less than the inhibition produced by unlabeled LDL. Adrenal gland uptake of {sup 111}In-LDL by hypercholesterolemic rabbits was reduced by 86% compared to the level of uptake observed in normal rabbits. These results were compatible with downregulation of adrenal LDL receptors in the hypercholesterolemic rabbits. Uptake of {sup 111}In-LDL in the atherosclerotic proximal aorta of hypercholesterolemic rabbits was 2.5 times higher than in normal rabbits. These results suggest that {sup 111}In-LDL has the potential to be a useful agent for external imaging of atherosclerotic lesions and lipoprotein biodistribution.

  3. Towards increased selectivity of drug delivery to cancer cells: development of a LDL-based nanodelivery system for hydrophobic photosensitizers

    NASA Astrophysics Data System (ADS)

    Buzova, Diana; Huntosova, Veronika; Kasak, Peter; Petrovajova, Dana; Joniova, Jaroslava; Dzurova, Lenka; Nadova, Zuzana; Sureau, Franck; Midkovsky, Pavol; Jancura, Daniel

    2012-10-01

    Low-density lipoproteins (LDL), a natural in vivo carrier of cholesterol in the vascular system, play a key role in the delivery of hydrophobic photosensitizers (pts) to tumor cells in photodynamic therapy (PDT) of cancer. To make this delivery system even more efficient, we have constructed a nano-delivery system by coating of LDL surface by polyethylene glycol (PEG) and dextran. Fluorescence spectroscopy and confocal fluorescence imaging were used to characterize redistribution of hypericin (Hyp), a natural potent pts, loaded in LDL/PEG and LDL/dextran complexes to free LDL molecules as well as to monitor cellular uptake of Hyp by U87-MG cells. It was shown than the redistribution process of Hyp between LDL molecules is significantly suppressed by dextran coating of LDL surface. On the other hand, PEG does not significantly influence this process. The modification of LDL molecules by the polymers does not inhibit their recognition by cellular LDL receptors. U-87 MG cellular uptake of Hyp loaded in LDL/PEG and LDL/dextran complexes appears to be similar to that one observed for Hyp transported by unmodified LDL particles. It is proposed that by polymers modified LDL molecules could be used as a basis for construction of a drug transport system for targeted delivery of hydrophobic drugs to cancer cells expressing high level of LDL receptors.

  4. Proportional counter device for detecting electronegative species in an air sample

    DOEpatents

    Allman, S.L.; Chen, F.C.; Chen, C.H.

    1994-03-08

    Apparatus for detecting an electronegative species comprises an analysis chamber, an inlet communicating with the analysis chamber for admitting a sample containing the electronegative species and an ionizable component, a radioactive source within the analysis chamber for emitting radioactive energy for ionizing a component of the sample, a proportional electron detector within the analysis chamber for detecting electrons emitted from the ionized component, and a circuit for measuring the electrons and determining the presence of the electronegative species by detecting a reduction in the number of available electrons due to capture of electrons by the electronegative species. 2 figures.

  5. Proportional counter device for detecting electronegative species in an air sample

    DOEpatents

    Allman, Steve L.; Chen, Fang C.; Chen, Chung-Hsuan

    1994-01-01

    Apparatus for detecting an electronegative species comprises an analysis chamber, an inlet communicating with the analysis chamber for admitting a sample containing the electronegative species and an ionizable component, a radioactive source within the analysis chamber for emitting radioactive energy for ionizing a component of the sample, a proportional electron detector within the analysis chamber for detecting electrons emitted from the ionized component, and a circuit for measuring the electrons and determining the presence of the electronegative species by detecting a reduction in the number of available electrons due to capture of electrons by the electronegative species.

  6. Correlation among electronegativity, cation polarizability, optical basicity and single bond strength of simple oxides

    SciTech Connect

    Dimitrov, Vesselin; Komatsu, Takayuki

    2012-12-15

    A suitable relationship between free-cation polarizability and electronegativity of elements in different valence states and with the most common coordination numbers has been searched on the basis of the similarity in physical nature of both quantities. In general, the cation polarizability increases with decreasing element electronegativity. A systematic periodic change in the polarizability against the electronegativity has been observed in the isoelectronic series. It has been found that generally the optical basicity increases and the single bond strength of simple oxides decreases with decreasing the electronegativity. The observed trends have been discussed on the basis of electron donation ability of the oxide ions and type of chemical bonding in simple oxides. - Graphical abstract: This figure shows the single bond strength of simple oxides as a function of element electronegativity. A remarkable correlation exists between these independently obtained quantities. High values of electronegativity correspond to high values of single bond strength and vice versa. It is obvious that the observed trend in this figure is closely related to the type of chemical bonding in corresponding oxide. Highlights: Black-Right-Pointing-Pointer A suitable relationship between free-cation polarizability and electronegativity of elements was searched. Black-Right-Pointing-Pointer The cation polarizability increases with decreasing element electronegativity. Black-Right-Pointing-Pointer The single bond strength of simple oxides decreases with decreasing the electronegativity. Black-Right-Pointing-Pointer The observed trends were discussed on the basis of type of chemical bonding in simple oxides.

  7. Formation of pre-sheath boundary layers in electronegative plasmas

    SciTech Connect

    Vitello, P., LLNL

    1998-05-01

    In electronegative plasmas Coulomb scattering between positive and negative ions can lead to the formation of a pre-sheath boundary layer containing the bulk of the negative ions. The negative ion boundary layer forms when momentum transfer from positive to negative ions dominates the negative ion acceleration from the electric field. This condition is met in Inductively Coupled Plasma reactors that operate at low pressure and high plasma density. Simulations of the GEC reactor for Chlorine and Oxygen chemistries using the INDUCT95 2D model are presented showing the pre-sheath boundary layer structure as a function of applied power and neutral pressure.

  8. Dynamics of electronegative plasmas for materials processing. Final report

    SciTech Connect

    Lichtenberg, A.J.; Lieberman, M.A.

    1996-12-31

    The purpose of this project is to study the equilibrium particle and energy balance and the heating mechanisms in electronegative r.f. discharges. Particular attention is given to the formation of non-Maxwellian electron distributions and their effect on the macroscopic parameters. The research includes theory, particle-in-cell simulation, and experimental investigations. The sheath heating theory and the simulation results developed for electropositive plasmas are used to guide the investigations. The investigation was centered on, but is not limited to, the study of oxygen feedstock gas in capacitively and inductively coupled r.f. discharges. 15 refs.

  9. Low-density lipoprotein (LDL)-antioxidant lignans from Myristica fragrans seeds.

    PubMed

    Kwon, Hyun Sook; Kim, Min-Jung; Jeong, Hyung Jae; Yang, Min Suk; Park, Ki Hun; Jeong, Tae-Sook; Lee, Woo Song

    2008-01-01

    Six diarylbutane lignans 1-5 and one aryltetralin lignan 6 were isolated from the methanol (95%) extracts of Myristica fragrans seeds and then 7-methyl ether diarylbutane lignan 4 has proven to be new a compound. Their compounds 1-7 were evaluated for LDL-antioxidant activity to identify the most potent LDL-antioxidant 3 with an IC50 value of 2.6 microM in TBARS assay. Due to its potency, compound 3 was tested for complementary in vitro investigations, such as lag time (140 min at 1.0 microM), relative electrophoretic mobility (REM) of ox-LDL (inhibition of 80% at 20 microM and 72% at 10 microM), and fragmentation of apoB-100 (inhibition of 93% at 20 microM) on copper-mediated LDL oxidation. In macrophage-mediated LDL oxidation, the TBARS formation was also inhibited by compound 3.

  10. Selective uptake and efflux of cholesteryl linoleate in LDL by macrophages expressing 12/15-lipoxygenase

    SciTech Connect

    Takahashi, Yoshitaka . E-mail: ytaka@fhw.oka-pu.ac.jp; Zhu, Hong; Xu, Wanpeng; Murakami, Takashi; Iwasaki, Tadao; Hattori, Hiroaki; Yoshimoto, Tanihiro

    2005-12-09

    Oxidation of low density lipoprotein (LDL) is a critical step for airtightness, and the role of the 12/15-lipoxygenase (12/15-Lox) as well as LDL receptor-related protein (Lp) expressed in macrophages in this process has been suggested. The oxygenation of cholesteryl linoleate in LDL by mouse macrophage-like Joe.1 cells over expressing 12/15-Lox was inhibited by an anti-Lp antibody but not by an anti-LDL receptor antibody. When the cells were incubated with LDL double-labeled by [{sup 3}H]cholesteryl linoleate and [{sup 125}I]apo B, association with the cells of [{sup 3}H]cholesteryl linoleate expressed as LDL protein equivalent exceeded that of [{sup 125}I]apo B, indicating selective uptake of [{sup 3}H]cholesteryl linoleate from LDL to these cells. An anti-Lp antibody inhibited the selective uptake of [{sup 3}H]cholesteryl ester by 62% and 81% with the 12/15-Lox-expressing cells and macrophages, respectively. Furthermore, addition of LDL to the culture medium of the [{sup 3}H]cholesteryl linoleate-labeled 12/15-Lox-expressing cells increased the release of [{sup 3}H]cholesteryl linoleate to the medium in LDL concentration- and time-dependent manners. The transport of [{sup 3}H]cholesteryl linoleate from the cells to LDL was also inhibited by an anti-Lp antibody by 75%. These results strongly suggest that Lp contributes to the LDL oxidation by 12/15-Lox in macrophages by selective uptake and efflux of cholesteryl ester in the LDL particle.

  11. Boundary conditions for electropositive and electronegative radio-frequency sheaths

    NASA Astrophysics Data System (ADS)

    Sobolewski, Mark

    2016-09-01

    Plasma sheaths play a dominant role in determining ion bombardment energies. To optimize plasma processes, sheaths must be understood and carefully controlled, which requires predictive models. One very efficient approach is to only model the sheath, excluding the bulk plasma. This approach, however, requires boundary conditions at the plasma/sheath boundary. Models that use the step approximation for electron density require initial ion velocities. More exact models with Boltzmann electrons (and, for electronegative discharges, negative ions) require the electron temperature (and the temperature and relative density of negative ions). It is often assumed that these boundary conditions have negligible effects on ion energies, but, for certain conditions in radio-frequency sheaths, this is not true. Analytic models as well as numerical simulations show that, at low frequencies (<= 1 MHz) and high bias voltages, the amplitude of the low-energy peak in ion energy distributions (IEDs) at the electrode is very sensitive to the boundary conditions. By measuring IEDs and sheath voltage waveforms, we obtain the most appropriate values of the boundary conditions for electropositive (Ar) as well as electronegative (CF4) discharges and insight into their presheath dynamics.

  12. E × B probe measurements in molecular and electronegative plasmas.

    PubMed

    Renaud, D; Gerst, D; Mazouffre, S; Aanesland, A

    2015-12-01

    This paper reports on the design, the building, the calibration, and the use of a compact E × B probe that acts as a velocity filter or a mass filter for ion species. A series of measurements has been performed in the discharge and in the beam of the PEGASES (Plasma Propulsion with Electronegative GASES) ion source. PEGASES is a unique inductively coupled radio-frequency source able to generate a beam of positive and negative ions when operated with an electronegative gas. In this study, experiments have been carried out with SF6. Calibrated E × B probe spectra indicate that the diagnostic tool can be used to determine the ion velocity and the plasma composition even when many molecular fragments are present. In addition, the probe is able to detect both positive and negative ions. Measurements show a large variety of positively charged ions coming from SF6. Conversely, the beam is solely composed of F(-) and SF6(-) negative ions in compliance with computer simulations.

  13. Extraction of negative ions from pulsed electronegative capacitively coupled plasmas

    SciTech Connect

    Agarwal, Ankur; Rauf, Shahid; Collins, Ken

    2012-08-01

    Charge buildup during plasma etching of dielectric features can lead to undesirable effects, such as notching, bowing, and twisting. Pulsed plasmas have been suggested as a method to achieve charge-free plasma etching. In particular, electronegative plasmas are attractive as the collapse of the plasma potential during the after-glow period of pulsed capacitively coupled plasmas (CCPs) can allow for extraction of negative ions into the feature. The extraction of negative ions in the after-glow of pulsed CCPs sustained in CF{sub 4} containing gas mixtures is computationally investigated. In this paper, the consequences of pulse frequency and gas chemistry on negative ion flux to the wafer are discussed. A low negative ion flux to the wafer was observed only in the late after-glow period of low pulse frequencies. The negative ion flux was found to significantly increase with the addition of highly electronegative gases (such as thermally attaching Cl{sub 2}) even at a high pulse frequency of 10 kHz. As the production of negative ions during the after-glow diminishes, alternative strategies to enhance the flux were also pursued. The flux of negative ions was found to increase by the addition of a pulsed dc voltage on the top electrode that is 180 Degree-Sign out-of-phase with the rf pulse.

  14. E × B probe measurements in molecular and electronegative plasmas

    NASA Astrophysics Data System (ADS)

    Renaud, D.; Gerst, D.; Mazouffre, S.; Aanesland, A.

    2015-12-01

    This paper reports on the design, the building, the calibration, and the use of a compact E × B probe that acts as a velocity filter or a mass filter for ion species. A series of measurements has been performed in the discharge and in the beam of the PEGASES (Plasma Propulsion with Electronegative GASES) ion source. PEGASES is a unique inductively coupled radio-frequency source able to generate a beam of positive and negative ions when operated with an electronegative gas. In this study, experiments have been carried out with SF6. Calibrated E × B probe spectra indicate that the diagnostic tool can be used to determine the ion velocity and the plasma composition even when many molecular fragments are present. In addition, the probe is able to detect both positive and negative ions. Measurements show a large variety of positively charged ions coming from SF6. Conversely, the beam is solely composed of F- and SF 6- negative ions in compliance with computer simulations.

  15. Antioxidant effects of Citrus aurantifolia (Christm) juice and peel extract on LDL oxidation.

    PubMed

    Boshtam, Maryam; Moshtaghian, Jamal; Naderi, Gholamali; Asgary, Seddigheh; Nayeri, Hashem

    2011-07-01

    We studied the antioxidant effects of fresh juice and peel extract of Citrus aurantifolia (Christm). Low density lipoprotein (LDL) was separated from one hypercholesterolemic human serum by modified Bronzert and Brewer procedure. Oxidation of LDL was measured at 234 nm against 0, 5, 10, 20, 25, 30 and 40 μl of fresh lime juice and 0, 5, 10, 15 and 20 μl of peel polyphenolic extract solution in DMSO. 5 μl of lime juice didn't change LDL oxidation. 10 μl of juice inhibited LDL oxidation, and with increasing the juice concentration, LDL was oxidized faster. The higher concentrations of peel extract prevented LDL oxidation better than the lower ones. Both juice and peel demonstrated antioxidant properties, but the excessive consumption of lime juice seems not to be beneficial. Regarding the intensity and type of flavonoids, lime juice and peel may show different effects.

  16. Long-Term Treatment of Native LDL Induces Senescence of Cultured Human Endothelial Cells

    PubMed Central

    Oh, Sung-Tack; Park, Hoon; Yoon, Hyun Joong

    2017-01-01

    The study aimed to evaluate whether the treatment of primary cultured human endothelial cells with native low-density lipoprotein (nLDL) could induce their senescence and to uncover some of the putative mechanisms involved. For this purpose, human umbilical vein endothelial cells (HUVECs) were subcultured and/or continuously cultured with nLDL (0, 2, 5, and 10 μg protein/mL), for up to 9 days. The results indicated that nLDL inhibited the proliferation of HUVECs by arresting the cell cycle at G1 phase. The G1-arrested cells showed increase in cytosolic senescence-associated-β-galactosidase (SA-β-Gal) activity, a biomarker of cellular senescence. The causative factor of the cellular senescence was nLDL itself and not oxidized LDL (oxLDL), since blocking LDL receptor (LDLR) with the anti-LDLR antibody opposed the nLDL-induced increase of SA-β-Gal activity and decrease of cellular proliferation. In addition, nLDL-induced cellular senescence by inhibiting the phosphorylation of pRb (G1 arrest) via p53 as well as p16 signal transduction pathways. G1 phase arrest of the senescent cells was not overcome by nLDL removal from the culture medium. Moreover, the nLDL-treated cells produced reactive oxygen species (ROS) dose- and time-dependently. These results suggested, for the first time, that long-term treatment of nLDL could induce the premature senescence of endothelial cells. PMID:28197300

  17. LDL density and oxidation are modulated by PON1 promoter genotype in patients with Alzheimer's disease.

    PubMed

    Cagnin, Annachiara; Leon, Alberta; Vianello, Daniela; Colavito, Davide; Favaretto, Silvia; Zarantonello, Giulia; Stecca, Anna; Ermani, Mario; Zambon, Alberto

    2013-01-01

    Cholesterol metabolism alteration is a hot topic in the field of Alzheimer's disease (AD). However, data on plasma lipoproteins cholesterol distribution and oxidation in AD and their possible genetic determinants are lacking. The paraoxonase-1 (PON1) gene -107C/T promoter polymorphisms have been found associated with AD. One of the fundamental functions of PON1 enzyme is the inhibition of low-density lipoproteins (LDL) oxidation. We therefore evaluated plasma lipoprotein profile and LDL density and oxidation in late-onset AD patients and healthy elderly subjects, without neuroimaging evidence of cerebrovascular lesions and not on lipid-lowering treatment, and their interaction with PON1 -107C/T and apolipoprotein E (APOE) genotypes. Mean plasma total cholesterol and LDL levels were higher in AD than controls (p < 0.05). Lipoproteins cholesterol distribution shifted toward a greater prevalence of smaller, denser LDL (sd-LDL, p < 0.05) only in AD patients with PON1 -107TT genotype, who also showed increased plasma levels of oxidized LDL (ox-LDL, p = 0.02). A significant association was observed between sd-LDL and ox-LDL levels (p < 005) in AD patients. APOE genotype did not modulate lipoprotein distribution. Increased levels of sd-LDL and ox-LDL particles in the AD PON1 TT patients could be explained by the combined effect of an AD-related pro-oxidant milieu and an ineffective PON1 gene polymorphism-related antioxidant capacity. The functional correlate of the association between PON1 -107C/T polymorphism and AD may be the abnormal modulation of LDL oxidation. Ox-LDL may amplify the processes of endothelial injury promoted by vascular amyloid deposition, which represents one of the potential pathways explaining the cross-road between vascular and neurodegenerative pathomechanisms in AD.

  18. LOX-1 in macrophage migration in response to ox-LDL and the involvement of calpains.

    PubMed

    Wang, Xianwei; Ding, Zufeng; Lin, Juntang; Guo, Zhikun; Mehta, Jawahar L

    2015-11-06

    Previous studies have shown that oxidized low-density lipoprotein (ox-LDL) inhibits macrophage migration, but the precise mechanisms remain unclear. Lectin-like ox-LDL receptor-1 (LOX-1) is a scavenger receptor that is expressed in macrophages and binds ox-LDL. Calpains, a family of calcium-dependent proteases, influence several aspects of cell migration. In this study, we investigated the role of LOX-1 in macrophage migration in response to ox-LDL and the involvement of calpains in this process. Peritoneal macrophages from wild type C57BL/6 mice were exposed to different concentrations of ox-LDL (1-20 μg/mL), and expression of LOX-1 and calpain-1 and -2, cell migration and intracellular calcium (Ca(2+)in) were measured. Our results showed that ox-LDL stimulated LOX-1 and calpain-2 expression, and inhibited calpain-1 expression in a dose- and time-dependent manner. Further, ox-LDL inhibited macrophage migration and increased Ca(2+)in concentration in macrophages. To further elucidate the role of LOX-1 in ox-LDL-impaired macrophage migration, we isolated peritoneal macrophages from LOX-1 knockout mice, and treated them with ox-LDL. Interestingly, calpain-1 expression was much higher, and calpain-2 expression was lower in LOX-1 knockout macrophages than in wild-type macrophages following exposure to ox-LDL. LOX-1 deletion significantly improved macrophage migration and decreased Ca(2+)in concentration. These data indicate that LOX-1 is, at least in part, responsible for the inhibitory effect of ox-LDL on macrophage migration and this process involves calpain-1 and -2.

  19. α5β1 Integrin Signaling Mediates Oxidized LDL-Induced Inflammation and Early Atherosclerosis

    PubMed Central

    Yurdagul, Arif; Green, Jonette; Albert, Patrick; McInnis, Marshall C.; Mazar, Andrew P.; Orr, A. Wayne

    2014-01-01

    Objective Endothelial cell activation drives early atherosclerotic plaque formation. Both fibronectin deposition and accumulation of oxidized LDL (oxLDL) occur early during atherogenesis and both are implicated in enhanced endothelial cell activation. However, interplay between these responses has not been established. The objective of our study was to determine whether endothelial matrix composition modulates the inflammatory properties of oxLDL. Approach and Results We now show that oxLDL-induced NF-κB activation, proinflammatory gene expression, and monocyte binding is significantly enhanced when endothelial cells are attached to fibronectin compared to basement membrane proteins. This enhanced response does not result from altered oxLDL receptor expression, oxLDL uptake, or reactive oxygen species production, but instead results from oxLDL-induced activation of the fibronectin-binding integrin α5β1. Preventing α5β1 signaling (blocking antibodies, knockout cells) inhibits oxLDL-induced NF-κB activation and VCAM-1 expression. Furthermore, oxLDL-drives α5β1-dependent integrin signaling through the focal adhesion kinase (FAK) pathway and FAK inhibition (PF-573228, siRNA) blunts oxLDL-induced NF-κB activation, VCAM-1 expression, and monocyte adhesion. Lastly, treatment with the α5β1 signaling inhibitor, ATN-161, significantly blunts atherosclerotic plaque development in ApoE deficient mice, characterized by reduced VCAM-1 expression and macrophage accumulation without affecting fibrous cap size. Conclusions Our data suggest that α5β1-mediated crosstalk between fibronectin and oxidized LDL regulates inflammation in early atherogenesis and therapeutics that inhibit α5 integrins may reduce inflammation without adversely affecting plaque structure. PMID:24833794

  20. Ion drag force in plasmas at high electronegativity.

    PubMed

    Denysenko, I; Yu, M Y; Stenflo, L; Xu, S

    2005-07-01

    The electric as well as the positive- and negative-ion drag forces on an isolated dust grain in an electronegative plasma are studied for large negative-ion densities, when the negative ions are not Boltzmann distributed. The investigation is carried out for submicrometer dust particles, so that the theory of Coulomb scattering is applicable for describing ion-dust interaction. Among the forces acting on the dust grain, the negative-ion drag force is found to be important. The effects of the negative-ion density, neutral-gas pressure, and dust-grain size on the forces are also considered. It is shown that by increasing the density of the negative ions one can effectively manipulate the dust grains. Our results imply that both dust voids and balls can be formed.

  1. Experimental and simulation study of capacitively coupled electronegative discharges

    NASA Astrophysics Data System (ADS)

    Derzsi, Aranka

    2016-09-01

    The application of tailored voltage waveforms, generated by using multiple harmonics of a base frequency, for the excitation of capacitive RF discharges has been recently introduced as a new method to control the ion flux and ion energy distribution at the electrodes. In plasma processing of surfaces complex mixtures of electronegative, reactive gases (e.g. CF4, O2) are usually required. Therefore, the question of whether this new approach to control ion properties can be applied efficiently to such systems is of exceptional importance. Here the electron heating and ionization dynamics, the possibilities and limitations of the efficient control of plasma parameters by voltage waveform tailoring in low-pressure capacitively coupled electronegative discharges are presented. The focus is on geometrically symmetric O2 plasmas, which are investigated by PIC/MCC simulations and experimental methods. O2 discharges driven by impulse-type and sawtooth-type voltage waveforms composed of a maximum of four consecutive harmonics are studied. Experimental results on the dc self-bias voltage, as well as the spatiotemporal distribution of the plasma emission are compared with simulation data for a wide range of operating conditions (fundamental driving frequencies of 5 MHz - 15 MHz, at pressures of 50 mTorr - 700 mTorr). Transitions between electron power absorption due to sheath expansion and the drift-ambipolar mode were induced both by changing the number of harmonics or by changing the gas pressure. A good agreement between simulation and experiment is found, which shows that the collision-reaction model for O2 discharges underlying the simulations describes reasonably the complicated chemistry of oxygen plasmas. An investigation of the dependence of the discharge characteristics on the surface destruction coefficient of the O2(a1Δg) singlet metastable molecules revealed the crucial role of these species, which strongly affects the negative ion balance of the plasma.

  2. A Semimetal Nanowire Rectifier: Balancing Quantum Confinement and Surface Electronegativity.

    PubMed

    Sanchez-Soares, Alfonso; Greer, James C

    2016-12-14

    For semimetal nanowires with diameters on the order of 10 nm, a semimetal-to-semiconductor transition is observed due to quantum confinement effects. Quantum confinement in a semimetal lifts the degeneracy of the conduction and valence bands in a "zero" gap semimetal or shifts energy levels with a "negative" overlap to form conduction and valence bands. For semimetal nanowires with diameters less than 10 nm, the band gap energy can be significantly larger than the thermal energy at room temperature resulting in a new class of semiconductors suitable for nanoelectronics. As a nanowire's diameter is reduced, its surface-to-volume ratio increases rapidly leading to an increased impact of surface chemistry on its electronic structure. Energy level shifts to states in the vicinity of the Fermi energy with varying surface electronegativity are shown to be comparable in magnitude to quantum confinement effects arising in nanowires with diameters of a few nanometer; these two effects can counteract one another leading to semimetallic behavior at nanowire cross sections at which confinement effects would otherwise dominate. Abruptly changing the surface terminating species along the length of a nanowire can lead to an abrupt change in the surface electronegativity. This can result in the formation of a semimetal-semiconductor junction within a monomaterial nanowire without impurity doping nor requiring the formation of a heterojunction. Using density functional theory in tandem with a Green's function approach to determine electronic structure and charge transport, respectively, current rectification is calculated for such a junction. Current rectification ratios of the order of 10(3)-10(5) are predicted at applied biases as low as 300 mV. It is concluded that rectification can be achieved at essentially molecular length scales with conventional biasing, while rivaling the performance of macroscopic semiconductor diodes.

  3. Measurement of electronegativity at different laser wavelengths: accuracy of Langmuir probe assisted laser photo-detachment

    NASA Astrophysics Data System (ADS)

    Sirse, N.; Oudini, N.; Bendib, A.; Ellingboe, A. R.

    2016-08-01

    Langmuir probe (LP) assisted pulsed laser photo-detachment (LPD) of negative ions is one of the frequently used diagnostic techniques in electronegative plasmas. The technique is based on measuring the rise in electron saturation current following photo-detachment. During the photo-detachment process it is assumed that the background electron parameters (temperature and density) remain unchanged in the laser channel and the photo-detached electrons thermalize instantaneously with the background electrons (same temperature). Therefore, the measured electronegativity should be independent of laser wavelengths. However, our recent simulation results (2015 Phys. Plasmas 22 073509) demonstrates a failure of these assumptions and suggests that the measured rise in electron saturation current has a dependence on the laser wavelength. This letter presents experimental evidence in support of these simulation results. In this work, photo-detachment is performed at two different laser wavelengths in an oxygen inductively coupled plasma discharge. Electronegativity measured by LP assisted LPD is compared with those obtained by the hairpin probe (HPP) assisted LPD which is based on quasi-neutrality assumption. The experimental results reveal that the electronegativities measured by LP assisted LPD are affected by the laser wavelength, whereas, electronegativities measured by HPP assisted LPD are almost independent. The discrepancy between the measurements is higher at high electronegativities. In conclusion, the experimental results validate the weakness of assumptions to estimate electronegativity from LPD combined with LP and therefore emphasizes the need of a more realistic model to analyze raw data or an alternate solution is to utilize HPP.

  4. SIRT1 regulates accumulation of oxidized LDL in HUVEC via the autophagy-lysosomal pathway.

    PubMed

    Zhang, Yanlin; Sun, Juanjuan; Yu, Xiaoyan; Shi, Luyao; Du, Wenxiu; Hu, Lifang; Liu, Chunfeng; Cao, Yongjun

    2016-01-01

    Autophagy is involved in the degradation of oxidized low-density lipoprotein (ox-LDL) in human umbilical vein endothelial cells (HUVECs). Sirtuin1 (SIRT1), a new anti-atherosclerotic factor, can induce autophagy in cardiac myocytes. In the present study, we observed the effect of SIRT1 on the accumulation of ox-LDL in HUVECs, and elucidated whether its effect is relative with the autophagy-lysosomal pathway. The results showed that treatment with either SIRT1 siRNA or SIRT1 inhibitor nicotinamide (NAM) increased Dil-labelled-ox-LDL (Dil-ox-LDL) accumulation in HUVECs, and the SIRT1 inducer resveratrol (RSV) decreased it. Knockdown of autophagy-related protein 5 or inhibit the lysosomal degradation by chloroquine (CQ) decreased the effect of RSV. In HUVECs with ox-LDL, expression of LC3II and LC3 puncta was decreased by treatment with SIRT1 siRNA or NAM, but increased by RSV treatment; sequestosome 1 p62 expression showed the opposite effects. Moreover, Dil-ox-LDL combined with SIRT1 siRNA or NAM showed a much smaller degree of overlap of Lamp1 or Cathepsin D with Dil-ox-LDL than in cells with Dil-ox-LDL alone, and RSV treatment resulted in a greater degree of overlap. These results suggest that SIRT1 can decrease the accumulation of ox-LDL in HUVECs, and this effect is related to the autophagy-lysosomal pathway.

  5. Oxidized low density lipoprotein (LDL) affects hyaluronan synthesis in human aortic smooth muscle cells.

    PubMed

    Viola, Manuela; Bartolini, Barbara; Vigetti, Davide; Karousou, Evgenia; Moretto, Paola; Deleonibus, Sara; Sawamura, Tatsuya; Wight, Thomas N; Hascall, Vincent C; De Luca, Giancarlo; Passi, Alberto

    2013-10-11

    Thickening of the vessel in response to high low density lipoprotein(s) (LDL) levels is a hallmark of atherosclerosis, characterized by increased hyaluronan (HA) deposition in the neointima. Human native LDL trapped within the arterial wall undergoes modifications such as oxidation (oxLDL). The aim of our study is to elucidate the link between internalization of oxLDL and HA production in vitro, using human aortic smooth muscle cells. LDL were used at an effective protein concentration of 20-50 μg/ml, which allowed 80% cell viability. HA content in the medium of untreated cells was 28.9 ± 3.7 nmol HA-disaccharide/cell and increased after oxLDL treatment to 53.9 ± 5.6. OxLDL treatments doubled the transcripts of HA synthase HAS2 and HAS3. Accumulated HA stimulated migration of aortic smooth muscle cells and monocyte adhesiveness to extracellular matrix. The effects induced by oxLDL were inhibited by blocking LOX-1 scavenger receptor with a specific antibody (10 μg/ml). The cholesterol moiety of LDL has an important role in HA accumulation because cholesterol-free oxLDL failed to induce HA synthesis. Nevertheless, cholesterol-free oxLDL and unmodified cholesterol (20 μg/ml) induce only HAS3 transcription, whereas 22,oxysterol affects both HAS2 and HAS3. Moreover, HA deposition was associated with higher expression of endoplasmic reticulum stress markers (CHOP and GRP78). Our data suggest that HA synthesis can be induced in response to specific oxidized sterol-related species delivered through oxLDL.

  6. Genetic and metabolic influences on LDL subclasses

    SciTech Connect

    Krauss, R.M.; Rotter, J.I.; Lusis, A.J.

    1994-09-01

    Genetic and environmental factors influence LDL particle size and density, and expression of an atherogenic lipoprotein phenotype (ALP) characterized by predominance of small, dense LDL particles. Linkage of ALP the LDL receptor locus has been reported previously. Quantitative sib-pair relative-pair linkage methodologies were used to test for linkage of LDL particle size to candidate loci in 25 large pedigrees with familial coronary artery disease. Linkage to the LDL receptor gene locus was confirmed (p=0.008). Evidence was also obtained for linkage to the genes for apoCIII, cholesteryl ester transfer protein, and manganese superoxide dismutase. The results suggest multiple genetic determinants of LDL particle size that may involve different metabolic mechanisms giving rise to small, dense LDL and increased atherosclerosis risk.

  7. Electronegativities of the elements from density functional theory. I. The Hartree-Fock-Slater theory

    NASA Astrophysics Data System (ADS)

    Manoli, S.; Whitehead, M. A.

    1984-07-01

    Mathematical expressions for the electronegativities of the elements are derived exactly using the Hartree-Fock-Slater equations and Mulliken's definition of electronegativity. Relaxation effects are neglected. These equations are the same ones used by Bartolotti, Gadre, and Parr. They are generalized for the spin-polarized case and calculations are done for the elements helium to krypton. Results show that the spin-polarized ionization potentials are closer to experiment than the non-spin-polarized ones and that the trend in the electronegativities obtained from spin-polarized calculations is the same as the one obtained by Bartolotti et al. using a non-spin-polarized program.

  8. A novel functionalization method for carbon nanotubes to repel ox-LDL in treatments after stent placement.

    PubMed

    Santana, C I; Hoyos, L M; Pérez, J F; Bustamante, J; García, A G

    2017-10-01

    Carbon nanotubes (CNT) can be chemically modified by doping or functionalization to change the chemical and surface properties. These characteristic makes to CNT candidates for multiple applications including medical field in cardiovascular area. A novel method to CNT functionalization by formation of two compounds: α-bromoacid and the organic compound 2-(methacryloyloxy) ethyl phosphorylcholine (MPC), will be discussed in this article. According to results, CNT are suggested like candidates to repel oxidized low-density lipoproteins (ox-LDL) to prevent restenosis. The electronegative character on surface of functionalized CNT (F-CNT) is shown by wettability analysis observing a repellent behaviour in contact with ox-LDL after functionalization route. Here we analyse the toxicity of CNT and F-CNT on HepG2 cell line and find no damage to the cell membrane of HepG2 cells in concentration at doses below 1mg/ml. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Emerging low-density lipoprotein (LDL) therapies: Management of severely elevated LDL cholesterol--the role of LDL-apheresis.

    PubMed

    McGowan, Mary P

    2013-01-01

    Low-density lipoprotein (LDL)-apheresis is a Food and Drug Administration-approved treatment for patients with homozygous familial hypercholesterolemia (FH) or severe heterozygous FH. Based on electrochemical principles, it selectively removes apolipoprotein B-containing lipoproteins through extracorporeal precipitation with either heparin (Heparin-induced Extracorporeal LDL Precipitation, ie, HELP) or dextran sulfate (Liposorber). LDL-apheresis can lead to an acute decrease in LDL cholesterol (LDL-C) of 70%-80%, but there is a rapid rebound to baseline levels within approximately 2 weeks. LDL-apheresis is typically performed once-a-week in patients with homozygous FH and every other week in those with heterozygous FH to produce time-average LDL-C reductions of ≈ 40%. Side effects associated with LDL-apheresis include hypotension (later found to be due to concomitant use of angiotensin-converting enzyme inhibitors), nausea/vomiting, flushing, angina, and fainting. Posttreatment bleeding can occur secondary to heparin used during the procedure. Challenges associated with LDL-apheresis include vascular access often requiring an arteriovenous fistula (fistulas may clot and require revision over time), the time associated with each treatment session (2-4 hours), the frequency of treatment, and the scarcity of medical centers which perform LDL-apheresis. Given the nature of LDL-apheresis, randomized placebo controlled trials are nearly impossible, and virtually all studies of clinical benefit have been non-randomized investigations of small numbers of subjects. Nonetheless, results from those studies support the benefits of LDL-C reduction for reducing coronary atherosclerosis and cardiovascular events.

  10. Synthetic low-density lipoprotein (sLDL) selectively delivers paclitaxel to tumor with low systemic toxicity

    PubMed Central

    Su, Hai-Tao; Li, Xin; Liang, De-Sheng; Qi, Xian-Rong

    2016-01-01

    Low density lipoprotein (LDL), which is a principal carrier for the delivery of cholesterol, has been used as a great candidate for the delivery of drugs to tumor based on the great requirements for cholesterol of many cancer cells. Mimicking the structure and composition of LDL, we designed a synthetic low-density lipoprotein (sLDL) to encapsulate paclitaxel-alpha linolenic acid (PALA) for tumor therapy. The PALA loaded sLDL (PALA-sLDL) and PALA-loaded microemulsion (PALA-ME, without the binding domain for LDLR) displayed uniform sizes with high drug loading efficiency (> 90%). In vitro studies demonstrated PALA-sLDL exhibited enhanced cellular uptake capacity and better cytotoxicity to LDLR over-expressed U87 MG cells as compared to PALA-ME. The uptake mechanisms of PALA-sLDL were involved in a receptor mediated endocytosis and macropinocytosis. Furthermore, the in vivo biodistribution and tumor growth inhibition studies of PALA-sLDL were investigated in xenograft U87 MG tumor-bearing mice. The results showed that PALA-sLDL exhibited higher tumor accumulation than PALA-ME and superior tumor inhibition efficiency (72.1%) compared to Taxol® (51.2%) and PALA-ME (58.8%) but with lower toxicity. These studies suggested that sLDL is potential to be used as a valuable carrier for the selective delivery of anticancer drugs to tumor with low systemic toxicity. PMID:27409176

  11. An Improved Experiment to Illustrate the Effect of Electronegativity on Chemical Shift.

    ERIC Educational Resources Information Center

    Boggess, Robert K.

    1988-01-01

    Describes a method for using nuclear magnetic resonance to observe the effect of electronegativity on the chemical shift of protons in similar compounds. Suggests the use of 1,3-dihalopropanes as samples. Includes sample questions. (MVL)

  12. An Improved Experiment to Illustrate the Effect of Electronegativity on Chemical Shift.

    ERIC Educational Resources Information Center

    Boggess, Robert K.

    1988-01-01

    Describes a method for using nuclear magnetic resonance to observe the effect of electronegativity on the chemical shift of protons in similar compounds. Suggests the use of 1,3-dihalopropanes as samples. Includes sample questions. (MVL)

  13. Is Electronegativity a Useful Descriptor for the "Pseudo-Alkali-Metal" NH4?

    SciTech Connect

    Whiteside, Alexander; Xantheas, Sotiris S.; Gutowski, Maciej S.

    2011-11-18

    Molecular ions in the form of "pseudo-atoms" are common structural motifs in chemistry, with properties that are transferrable between different compounds. We have determined the electronegativity of the "pseudo-alkali metal" ammonium (NH4) and evaluated its reliability as a descriptor in comparison to the electronegativities of the alkali metals. The computed properties of its binary complexes with astatine and of selected borohydrides confirm the similarity of NH4 to the alkali metal atoms, although the electronegativity of NH4 is relatively large in comparison to its cationic radius. We paid particular attention to the molecular properties of ammonium (angular anisotropy, geometric relaxation, and reactivity), which can cause deviations from the behaviour expected of a conceptual "true alkali metal" with this electronegativity. These deviations allow for the discrimination of effects associated with the polyatomic nature of NH4.

  14. Electronegative Plasma Equilibria with Spatially-Varying Ionization

    NASA Astrophysics Data System (ADS)

    Lieberman, M. A.; Kawamura, E.; Lichtenberg, A. J.

    2012-10-01

    Electronegative inductive discharges in higher pressure ranges typically exhibit localized ionization near the coil structure, with decay of the ionization into the central discharge. We use a two-dimensional fluid code [1] with chlorine feedstock to determine the spatial profiles of the plasma parameters in a cylindrical transformer-coupled plasma device excited by a planar coil. To compare with one-dimensional (1D) analytic modeling, the results are area-averaged. The ionization is found to decay roughly exponentially along the axial direction, allowing the ansatz of an exponentially decaying ionization to be used in a 1D computational model. The model captures the main features of the axial variations of the area-averaged fluid simulation, indicating that the main diffusion mechanisms act along the axial direction. A simple analytic global discharge model is developed, accounting for the asymmetric density and ionization profiles. The global model gives the scalings with power and pressure of volume-averaged densities, electron temperature, and ionization decay rate, also in reasonable agreement with the scalings obtained by averaging the simulation results. [4pt] [1] E. Kawamura, D.B. Graves, and M.A. Lieberman, Plasma Sources Sci. Technol. 20, 035009 (2012)

  15. Sheath formation criterion in magnetized electronegative plasmas with thermal ions

    SciTech Connect

    Hatami, M. M.; Shokri, B.

    2013-03-15

    Taking into account the effect of collisions and positive ion temperatures, the sheath formation criterion is investigated in a weakly magnetized electronegative plasma consisting of electrons, negative and positive ions by using the hydrodynamics equations. It is assumed that the electron and negative ion density distributions are the Boltzmann distribution with two different temperatures. Also, it is assumed that the velocity of positive ions at the sheath edge is not normal to the wall (oblique entrance). Our results show that a sheath region will be formed when the initial velocity of positive ions or the ion Mach number M lies in a specific interval with particular upper and lower limits. Also, it is shown that the presence of the magnetic field affects both of these limits. Moreover, as an practical application, the density distribution of charged particles in the sheath region is studied for an allowable value of M, and it is seen that monotonically reduction of the positive ion density distribution leading to the sheath formation occurs only when M lies between two above mentioned limits.

  16. The effect of HDL-bound and free PON1 on copper-induced LDL oxidation.

    PubMed

    Bayrak, Ahmet; Bayrak, Tülin; Bodur, Ebru; Kılınç, Kamer; Demirpençe, Ediz

    2016-09-25

    Oxidative modification of LDL plays an important role in the development of atherosclerosis. High-density lipoprotein (HDL) confers protection against atherosclerosis and the antioxidative properties of paraoxonase 1 (PON1) has been suggested to contribute to this effect of HDL. The PON1 exist in two major polymorphic forms (Q and R), which regulate the concentration and activity of the enzyme and alter its ability to prevent lipid oxidation. However, the association of Q192R polymorphism with PON1's capacity to protect against LDL lipoperoxidation is controversial. The aim of this study was to evaluate the effects of the purified PON1 Q192R and the partially purified HDL-bound PON1 Q192R isoenzymes (HDL-PON1 Q192R) on LDL oxidation, with respect to their arylesterase/homocysteine thiolactonase (HTLase) activities. Cupric ion-induced LDL oxidation was reduced up to 48% by purified PON1 Q192, but only 33% by an equivalent activity of PON1 R192. HDL-PON1 Q192 isoenzyme caused a 65% reduction, whereas HDL-PON1 R192 isoenzyme caused only 46% reduction in copper ion-induced LDL oxidation. These findings reflect the fact that PON1 Q and PON1 R allozymes may have different protective characteristics against LDL oxidation. The protection against LDL oxidation provided by HDL-PON1 Q192R isoenzymes is more prominent than the purified soluble enzymes. Inhibition of the Ca(+2)-dependent PON1 Q192R arylesterase/HTLase by the metal chelator EDTA, did not alter PON1's ability to inhibit LDL oxidation. These studies indicate that the active site involvement of the purified enzyme is not similar to the HDL-bound one, in terms of both PON1 arylesterase/HTLase activity and the protection of LDL from copper ion-induced oxidation. Moreover, PON1's ability to protect LDL from oxidation does not seem to require calcium.

  17. Atheroprotective effect of oleoylethanolamide (OEA) targeting oxidized LDL.

    PubMed

    Fan, Angran; Wu, Xiaofeng; Wu, Huijuan; Li, Long; Huang, Rui; Zhu, Yueyong; Qiu, Yan; Fu, Jin; Ren, Jie; Zhu, Chenggang

    2014-01-01

    Dietary fat-derived lipid oleoylethanolamide (OEA) has shown to modulate lipid metabolism through a peroxisome proliferator-activated receptor-alpha (PPAR-α)-mediated mechanism. In our study, we further demonstrated that OEA, as an atheroprotective agent, modulated the atherosclerotic plaques development. In vitro studies showed that OEA antagonized oxidized LDL (ox-LDL)-induced vascular endothelial cell proliferation and vascular smooth muscle cell migration, and suppressed lipopolysaccharide (LPS)-induced LDL modification and inflammation. In vivo studies, atherosclerosis animals were established using balloon-aortic denudation (BAD) rats and ApoE(-/-) mice fed with high-caloric diet (HCD) for 17 or 14 weeks respectively, and atherosclerotic plaques were evaluated by oil red staining. The administration of OEA (5 mg/kg/day, intraperitoneal injection, i.p.) prevented or attenuated the formation of atherosclerotic plaques in HCD-BAD rats or HCD-ApoE(-/-) mice. Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of PPAR-α and downregulated the expression of M-CFS, an atherosclerotic marker, and genes involved in oxidation and inflammation, including iNOS, COX-2, TNF-α and IL-6. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti-atherosclerosis drug.

  18. Atheroprotective Effect of Oleoylethanolamide (OEA) Targeting Oxidized LDL

    PubMed Central

    Wu, Huijuan; Li, Long; Huang, Rui; Zhu, Yueyong; Qiu, Yan; Fu, Jin; Ren, Jie; Zhu, Chenggang

    2014-01-01

    Dietary fat-derived lipid oleoylethanolamide (OEA) has shown to modulate lipid metabolism through a peroxisome proliferator-activated receptor-alpha (PPAR-α)-mediated mechanism. In our study, we further demonstrated that OEA, as an atheroprotective agent, modulated the atherosclerotic plaques development. In vitro studies showed that OEA antagonized oxidized LDL (ox-LDL)-induced vascular endothelial cell proliferation and vascular smooth muscle cell migration, and suppressed lipopolysaccharide (LPS)-induced LDL modification and inflammation. In vivo studies, atherosclerosis animals were established using balloon-aortic denudation (BAD) rats and ApoE-/- mice fed with high-caloric diet (HCD) for 17 or 14 weeks respectively, and atherosclerotic plaques were evaluated by oil red staining. The administration of OEA (5 mg/kg/day, intraperitoneal injection, i.p.) prevented or attenuated the formation of atherosclerotic plaques in HCD-BAD rats or HCD-ApoE−/− mice. Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of PPAR-α and downregulated the expression of M-CFS, an atherosclerotic marker, and genes involved in oxidation and inflammation, including iNOS, COX-2, TNF-α and IL-6. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti-atherosclerosis drug. PMID:24465540

  19. Minimally oxidized LDL offsets the apoptotic effects of extensively oxidized LDL and free cholesterol in macrophages.

    PubMed

    Boullier, Agnès; Li, Yankun; Quehenberger, Oswald; Palinski, Wulf; Tabas, Ira; Witztum, Joseph L; Miller, Yury I

    2006-05-01

    Lipid-loaded macrophage-derived foam cells populate atherosclerotic lesions and produce many pro-inflammatory and plaque-destabilizing factors. An excessive accumulation of extensively oxidized low-density lipoprotein (OxLDL) or free cholesterol (FC), both of which are believed to be major lipid components of macrophages in advanced lesions, rapidly induces apoptosis in macrophages. Indeed, there is evidence of macrophage death in lesions, but how the surviving macrophages avoid death induced by OxLDL, FC, and other factors is not known. Minimally oxidized LDL (mmLDL), which is an early product of progressive LDL oxidation in atherosclerotic lesions, countered OxLDL-induced or FC-induced apoptosis and stimulated macrophage survival both in cell culture and in vivo. DNA fragmentation and caspase-3 activity in OxLDL-treated peritoneal macrophages were significantly reduced by coincubation with mmLDL. In a separate set of experiments, mmLDL significantly reduced annexin V binding to macrophages in which apoptosis was induced by FC loading. In both cellular models, mmLDL activated a pro-survival PI3K/Akt signaling pathway, and PI3K inhibitors, wortmannin and LY294002, eliminated the pro-survival effect of mmLDL. Immunohistochemical examination demonstrated phospho-Akt in murine atherosclerotic lesions. Minimally oxidized LDL, an early form of oxidized LDL in atherosclerotic lesions, may contribute to prolonged survival of macrophage foam cells in lesions via a PI3K/Akt-dependent mechanism.

  20. History of Discovery: The LDL Receptor

    PubMed Central

    Goldstein, Joseph L.; Brown, Michael S.

    2009-01-01

    Summary In this article, the history of the LDL receptor is recounted by its co-discoverers. Their early work on the LDL receptor explained a genetic cause of heart attacks and led to new ways of thinking about cholesterol metabolism. The LDL receptor discovery also introduced three general concepts to cell biology: receptor-mediated endocytosis, receptor recycling, and feedback regulation of receptors. The latter concept provides the mechanism by which statins selectively lower plasma LDL, reducing heart attacks and prolonging life. PMID:19299327

  1. Effects of olive leaves extract on LDL oxidation induced-CuSO(4) in vitro.

    PubMed

    Ahmadvand, Hassan; Bagheri, Shahrokh; Khosrobeigi, Ali; Boshtam, Maryam; Abdolahpour, Foad

    2012-07-01

    Oxidation of low-density lipoprotein (LDL) has been strongly implicated in the pathogenesis of atherosclerosis. The use of some natural antioxidant and herbal medicine may lead to the inhibition of production of oxidized LDL and may decrease both the development and the progression of atherosclerosis. The aim of this study was to investigate the effects of Olive leaves ethanol extract (OLE) on LDL oxidation induced-CuSO(4) quantitatively in vitro. Low-density lipoprotein was incubated with CuSO(4) and the formation of conjugated dienes and thiobarbituric acid reactive substances (TBARS). Inhibition of this Cu-induced oxidation was studied in the presence of vitamin E and various concentration of OLE. It was demonstrated that OLE reduced the formation of conjugated dienes and TBARS of LDL against oxidation in vitro (p<0.05). The inhibitory effects of the OLE on LDL oxidation were dose-dependent at concentrations ranging from (2μg/ml) to (200μg/ml). Moreover, we compared effects of OLE on LDL oxidation with vitamin E as positive control. This study showed that OLE is a source of potent antioxidants and prevented the oxidation of LDL in vitro and it may be suitable for use in food and pharmaceutical applications.

  2. Effects of MβCD on Lipoxygenase-Induced LDL Oxidation.

    PubMed

    Ao, Meiying; Chen, Yong

    2017-01-01

    Beta-cyclodextrin (β-CD) has been applied as drug/food carriers or potential drugs for treating some diseases. Most recently, some evidence indicated that methyl-β-cyclodextrin (MβCD) and 2-hydroxypropyl-β-cyclodextrin (2-HPβCD), two major derivatives of β-CD, may inhibit atherogenesis, implying that cyclodextrins also can be potential drugs for treating atherosclerosis. It is well known that modification (e.g. oxidation) of low-density lipoprotein (LDL) is one of the most critical steps of atherogenesis. Lipoxygenase, an enzyme able to be expressed by atherosclerosis-related vascular cells, is generally regarded as a possible in vivo agent of LDL oxidation. In this study, the effects of MβCD on LDL oxidation induced by lipoxygenase were investigated by measuring the electrophoretic mobility, conjugated diene formation, malondialdehyde (MDA) production, and amino group blockage of LDL. We found that the lipids depleted from LDL by MβCD could be oxygenated more readily by lipoxygenase whereas the lipoxygenase-induced oxidation of the remaining lipid-depleted LDL decreased. The data imply that MβCD has an inhibitory effect on lipoxygenase-induced LDL oxidation and probably helps to inhibit atherogenesis.

  3. Surface interactions involved in flashover with high density electronegative gases.

    SciTech Connect

    Hodge, Keith Conquest; Warne, Larry Kevin; Jorgenson, Roy Eberhardt; Wallace, Zachariah Red; Lehr, Jane Marie

    2010-01-01

    This report examines the interactions involved with flashover along a surface in high density electronegative gases. The focus is on fast ionization processes rather than the later time ionic drift or thermalization of the discharge. A kinetic simulation of the gas and surface is used to examine electron multiplication and includes gas collision, excitation and ionization, and attachment processes, gas photoionization and surface photoemission processes, as well as surface attachment. These rates are then used in a 1.5D fluid ionization wave (streamer) model to study streamer propagation with and without the surface in air and in SF6. The 1.5D model therefore includes rates for all these processes. To get a better estimate for the behavior of the radius we have studied radial expansion of the streamer in air and in SF6. The focus of the modeling is on voltage and field level changes (with and without a surface) rather than secondary effects, such as, velocities or changes in discharge path. An experiment has been set up to carry out measurements of threshold voltages, streamer velocities, and other discharge characteristics. This setup includes both electrical and photographic diagnostics (streak and framing cameras). We have observed little change in critical field levels (where avalanche multiplication sets in) in the gas alone versus with the surface. Comparisons between model calculations and experimental measurements are in agreement with this. We have examined streamer sustaining fields (field which maintains ionization wave propagation) in the gas and on the surface. Agreement of the gas levels with available literature is good and agreement between experiment and calculation is good also. Model calculations do not indicate much difference between the gas alone versus the surface levels. Experiments have identified differences in velocity between streamers on the surface and in the gas alone (the surface values being larger).

  4. Electronegativity and intrinsic disorder of preeclampsia-related proteins.

    PubMed

    Polanco, Carlos; Castañón-González, Jorge Alberto; Uversky, Vladimir N; Buhse, Thomas; Samaniego Mendoza, José Lino; Calva, Juan J

    2017-01-01

    Preeclampsia, hemorrhage, and infection are the leading causes of maternal death in underdeveloped countries. Since several proteins associated with preeclampsia are known, we conducted a computational study which evaluated the commonness and potential functionality of intrinsic disorder of these proteins and also made an attempt to characterize their origin. The origin of the preeclampsia-related proteins was assessed with a supervised technique, a Polarity Index Method (PIM), which evaluates the electronegativity of proteins based solely on their sequence. The commonness of intrinsic disorder was evaluated using several disorder predictors from the PONDR family, the charge-hydropathy plot (CH-plot) and cumulative distribution function (CDF) analyses, and using the MobiDB web-based tool, whereas potential functionality of intrinsic disorder was studied with the D2P2 resource and ANCHOR predictor of disorder-based binding sites, and the STRING tool was used to build the interactivity networks of the preeclampsia-related proteins. Peculiarities of the PIM-derived polar profile of the group of preeclampsia-related proteins were then compared with profiles of a group of lipoproteins, antimicrobial peptides, angiogenesis-related proteins, and the intrinsically disordered proteins. Our results showed a high graphical correlation between preeclampsia proteins, lipoproteins, and the angiogenesis proteins. We also showed that many preeclampsia-related proteins contain numerous functional disordered regions. Therefore, these bioinformatics results led us to assume that the preeclampsia proteins are highly associated with the lipoproteins group, and that some preeclampsia-related proteins contain significant amounts of functional disorders.

  5. [The inhibitory effects of antioxidant vitamins on serum oxLDL and experimental atherosclerosis of rabbits].

    PubMed

    Chen, D; Yang, T; Song, F; Ruan, G; Liu, S

    1997-12-01

    In order to study the inhibitory effects of antioxidant vitamins on serum (low oxidative density lipoproteins, oxLDL) and experimental atherosclerosis in rabbits, 20 rabbits were fed on cholesterol rich diet and antioxidant vitamins (vitamin E, vitamin C and beta carotene) for 12 weeks. oxLDL were tested by ELISA at the beginning of experiment and after 4 weeks 8 weeks. The results showed that supplement of antioxidant vitamins can decrease the oxLDL level significantly and inhibited development of atherosclerosis lesion around aorta in rabbits.

  6. LDL-Apheresis: Technical and Clinical Aspects

    PubMed Central

    Bambauer, Rolf; Bambauer, Carolin; Lehmann, Boris; Latza, Reinhard; Schiel, Ralf

    2012-01-01

    The prognosis of patients suffering from severe hyperlipidemia, sometimes combined with elevated lipoprotein (a) levels, and coronary heart disease refractory to diet and lipid-lowering drugs is poor. For such patients, regular treatment with low-density lipoprotein (LDL) apheresis is the therapeutic option. Today, there are five different LDL-apheresis systems available: cascade filtration or lipid filtration, immunoadsorption, heparin-induced LDL precipitation, dextran sulfate LDL adsorption, and the LDL hemoperfusion. There is a strong correlation between hyperlipidemia and atherosclerosis. Besides the elimination of other risk factors, in severe hyperlipidemia therapeutic strategies should focus on a drastic reduction of serum lipoproteins. Despite maximum conventional therapy with a combination of different kinds of lipid-lowering drugs, sometimes the goal of therapy cannot be reached. Hence, in such patients, treatment with LDL-apheresis is indicated. Technical and clinical aspects of these five different LDL-apheresis methods are shown here. There were no significant differences with respect to or concerning all cholesterols, or triglycerides observed. With respect to elevated lipoprotein (a) levels, however, the immunoadsorption method seems to be most effective. The different published data clearly demonstrate that treatment with LDL-apheresis in patients suffering from severe hyperlipidemia refractory to maximum conservative therapy is effective and safe in long-term application. PMID:22654591

  7. Carbamylated Low-Density Lipoprotein (cLDL)-Mediated Induction of Autophagy and Its Role in Endothelial Cell Injury

    PubMed Central

    Bose, Chhanda; Shah, Sudhir V.; Karaduta, Oleg K.

    2016-01-01

    Patients with chronic kidney disease (CKD) have high risk of cardiovascular complications. Plasma levels of carbamylated proteins produced by urea-derived isocyanate or thiocyanate are elevated in CKD patients and that they are significant predictors of cardiovascular events and all-cause mortality. Carbamylated LDL (cLDL) has pro-atherogenic properties and is known to affect major biological processes relevant to atherosclerosis including endothelial cell injury. The underlying mechanisms of cLDL-induced endothelial cell injury are not well understood. Although autophagy has been implicated in atherosclerosis, cLDL-mediated induction of autophagy and its role in endothelial cell injury is unknown. Our studies demonstrate that human coronary artery endothelial cells (HCAECs) respond to cLDL by specific induction of key autophagy proteins including LC3-I, beclin-1, Atg5, formation of lipid-conjugated LC3-II protein, and formation of punctate dots of autophagosome-associated LC3-II. We demonstrated that autophagy induction is an immediate response to cLDL and occurred in a dose and time-dependent manner. Inhibition of cLDL-induced autophagy by a specific siRNA to LC3 as well as by an autophagy inhibitor provided protection from cLDL-induced cell death and DNA fragmentation. Our studies demonstrate that autophagy plays an important role in cLDL-mediated endothelial cell injury and may provide one of the underlying mechanisms for the pathogenesis of cLDL-induced atherosclerosis in CKD patients. PMID:27973558

  8. Effect of young barley leaf extract and adlay on plasma lipids and LDL oxidation in hyperlipidemic smokers.

    PubMed

    Yu, Ya-Mei; Chang, Weng-Cheng; Liu, Chu-Sun; Tsai, Ching-Min

    2004-06-01

    Forty hyperlipidemic patients, smokers and non-smokers, were studied. Subjects received 15 g young barley leaf extract (BL) or 60 g adlay daily for four weeks. Overnight fasting blood samples were drawn immediately prior to and after four weeks of supplementation. Blood samples were analyzed for plasma lipid profiles and their susceptibility to low-density lipoprotein (LDL) oxidation. The plasma total and LDL-cholesterol (LDL-C) levels were reduced following treatment with either BL or adlay; furthermore, the lag phase of LDL oxidation increased after either supplementation. However, it seemed that BL had stronger antioxidative effect on the prevention of LDL oxidation than adlay. Our results also indicated that the antioxidative effect was less pronounced in smokers than in non-smokers. Therefore, supplementation with BL or adlay can decrease plasma lipids and inhibit LDL oxidation in hyperlipidemic smokers and/or non-smokers.

  9. Isorhamnetin prevent endothelial cell injuries from oxidized LDL via activation of p38MAPK.

    PubMed

    Bao, Meihua; Lou, Yijia

    2006-10-10

    The present investigation was undertaken to determine the protective effects of isorhamnetin on endothelial cell line EA.hy926 injuries induced by oxidized low-density lipoprotein (ox-LDL) and to uncover some of the underlying mechanisms of these effects. Indices such as cell viability, lactate dehydrogenase (LDH), and nitric oxide (NO) release were measured to evaluate the protective effects of isorhamnetin. 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, superoxide dismutase (SOD), superoxide and reactive oxygen species (ROS) generation were also detected to evaluate the antioxidant effects of isorhamnetin. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was used to confirm the expression of endothelial nitric oxide synthase (eNOS) mRNA and lectin-like ox-LDL receptor-1 mRNA. Western blotting was used to evaluate the protein expression of this receptor and eNOS, as well as p38-mitogen-activated protein kinase (p38MAPK) phosphorylation and NF-kappaB p65 translocation. As a result, cell viability decreased significantly (P<0.01) after 24 h treatment with ox-LDL, accompanied with apparent secretion disorders such as NO reduction and LDH increase. Pretreatment with isorhamnetin resulted in remarkable increase of cell viability (P<0.05) and modulation of secretion disorders mediated by ox-LDL in a concentration-dependent manner. Besides, ox-LDL led to upregulation of lectin-like ox-LDL receptor-1, phosphorylation of p38MAPK, translocation of NF-kappaB, and downregulation of the eNOS expression in endothelial cells. Isorhamnetin pretreatment inhibited the ox-LDL-induced downregulation of eNOS, upregulation of lectin-like ox-LDL receptor-1, phosphorylation of the p38MAPK and translocation of NF-kappaB. Moreover, isorhamnetin exhibited strong antioxidant activity, which was shown by its inhibition effects on ox-LDL-induced superoxide, ROS overproduction and significant SOD reduction. The data indicated the protective effects of isorhamnetin on

  10. Prevention by alpha-tocopherol and rutin of glutathione and ATP depletion induced by oxidized LDL in cultured endothelial cells.

    PubMed Central

    Schmitt, A.; Salvayre, R.; Delchambre, J.; Nègre-Salvayre, A.

    1995-01-01

    1. Oxidized low density lipoproteins (LDL) are thought to play an important role in atherogenesis. Mildly oxidized LDL are cytotoxic to cultured endothelial cells. Toxic doses of oxidized LDL promote the peroxidation of cellular lipids (beginning at 6 h and being maximal after 12 h of pulse with oxidized LDL) and glutathione and ATP depletion (beginning after 15 h of pulse and evolving concurrently with the cytotoxicity). 2. Antioxidants from 3 different classes (rutin, ascorbic acid and alpha-tocopherol) were compared as to their ability to inhibit the cytotoxic effect of oxidized LDL to endothelial cells. 3. Effective concentrations of alpha-tocopherol inhibited cellular lipid peroxidation, glutathione and ATP depletion and the cytotoxic effect. 4. Ascorbic acid was less effective than alpha-tocopherol and rutin, and exhibited a dose-dependent biphasic effect in the presence of oxidized LDL. 5. Effective concentrations of rutin inhibited glutathione and ATP depletion as well as cytotoxicity, but did not block cellular lipid peroxidation. This suggests that the glutathione and ATP depletion is directly correlated to the cytotoxicity of oxidized LDL, whereas cellular lipid peroxidation is probably not directly the cause of cellular damage leading to cell death. 6. The association of antioxidants of 3 different classes allowed the suppression of the biphasic effect of ascorbic acid and increased the efficacy of the protective effect. The potential consequences for prevention of the pathogenic role of oxidized LDL in endothelial injury are discussed. PMID:8640336

  11. OxLDL receptor chromatography from live human U937 cells identifies SYK(L) that regulates phagocytosis of oxLDL.

    PubMed

    Howard, Jeffrey C; Florentinus-Mefailoski, Angelique; Bowden, Peter; Trimble, William; Grinstein, Sergio; Marshall, John G

    2016-11-15

    The binding and activation of macrophages by microscopic aggregates of oxLDL in the intima of the arteries may be an important step towards atherosclerosis leading to heart attack and stroke. Microbeads coated with oxLDL were used to activate, capture and isolate the oxLDL receptor complex from the surface of live cells. Analysis of the resulting tryptic peptides by liquid chromatography and tandem mass spectrometry revealed the Spleen Tyrosine Kinase (SYK), and many of SYK's known interaction network including Fc receptors (FCGR2A, FCER1G and FCGR1A) Toll receptor 4 (TLR4), receptor kinases like EGFRs, as well as RNA binding and metabolism proteins. High-intensity precursor ions (∼9*E3 to 2*E5 counts) were correlated to peptides and specific phosphopeptides from long isoform of SYK (SYK-L) by the SEQUEST, OMSSA and X!TANDEM algorithms. Peptides or phosphopeptides from SYK were observed with the oxLDL-microbeads. Pharmacological inhibitors of SYK activity significantly reduced the engulfment of oxLDL microbeads in the presence of serum factors, but had little effect on IgG phagocytosis. Anti SYK siRNA regulated oxLD engulfment in the context of serum factors and or SYK-L siRNA significantly inhibited engulfment of oxLDL microbeads, but not IgG microbeads. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Acid Sphingomyelinase Mediates Oxidized-LDL Induced Apoptosis in Macrophage via Endoplasmic Reticulum Stress

    PubMed Central

    Zhao, Min; Pan, Wei; Shi, Rui-zheng; Bai, Yong-ping; You, Bo-yang; Zhang, Kai; Fu, Qiong-mei; Schuchman, Edward H.

    2016-01-01

    Aim: Macrophage apoptosis is a vital event in advanced atherosclerosis, and oxidized low-density lipoprotein (ox-LDL) is a major contributor to this process. Acid sphingomyelinase (ASM) and ceramide are also involved in the induction of apoptosis, particularly in macrophages. Our current study focuses on ASM and investigates its role in ox-LDL-induced macrophage apoptosis. Methods: Human THP-1 and mouse peritoneal macrophages were cultured in vitro and treated with ox-LDL. ASM activity and ceramide levels were quantified using ultra performance liquid chromatography. Protein and mRNA levels were analyzed using Western blot analysis and quantitative realtime PCR, respectively. Cell apoptosis was determined using Hoechst staining and flow cytometry. Results: Ox-LDL-induced macrophage apoptosis was triggered by profound endoplasmic reticulum (ER) stress, leading to an upregulation of ASM activity and ceramide levels at an early stage. ASM was inhibited by siRNA or desipramine (DES), and/or ceramide was degraded by recombinant acid ceramidase (AC). These events attenuated the effect of ox-LDL on ER stress. In contrast, recombinant ASM upregulated ceramide and ER stress. ASM siRNA, DES, recombinant AC, and ER stress inhibitor 4-phenylbutyric acid were blocked by elevated levels of C/EBP homologous protein (CHOP); ox-LDL induced elevated levels of CHOP. These events attenuated macrophage apoptosis. Conclusion: These results indicate that ASM/ceramide signaling pathway is involved in ox-LDL-induced macrophage apoptosis via ER stress pathway. PMID:26923251

  13. Pinoresinol Diglucoside Alleviates oxLDL-Induced Dysfunction in Human Umbilical Vein Endothelial Cells

    PubMed Central

    Zou, Zhipeng; Wang, Xiangfen; Ji, Xiaoping

    2016-01-01

    Atherosclerotic cardiovascular diseases are the leading causes of morbidity and mortality worldwide. Deposition of oxidized low-density lipoprotein (oxLDL) is one of the initiators and promoters of atherosclerosis. Eucommia lignans were shown to possess antihypertensive effects. This study aimed to investigate the effects of pinoresinol diglucoside (PD), a Eucommia lignan, on oxLDL-induced endothelial dysfunction. HUVECs were treated with oxLDL and/or PD followed by assessing radical oxygen species (ROS), apoptosis, nitrogen oxide (NO), malondialdehyde (MDA), and superoxide dismutase (SOD) activity with specific assays kits, mRNA levels with quantitative real-time polymerase chain reaction (PCR), and protein levels with western blot. PD abolished oxLDL-induced ROS and MDA production, apoptosis, upregulation of lectin-like oxidized LDL recptor-1 (LOX-1), intercellular Adhesion Molecule 1 (ICAM-1), and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), and activation of p38MAPK (mitogen-activated protein kinases)/NF-κB signaling. Meanwhile, PD alleviated oxLDL-caused inhibition of SOD activity, eNOS expression, and NO production. These data demonstrated that PD was effective in protecting endothelial cells from oxLDL-caused injuries, which guarantees further investigation on the clinical benefits of PD on cardiovascular diseases. PMID:28042303

  14. Redox and Lewis acid-base activities through an electronegativity-hardness landscape diagram.

    PubMed

    Das, Ranjita; Vigneresse, Jean-Louis; Chattaraj, Pratim Kumar

    2013-11-01

    Chemistry is the science of bond making and bond breaking which requires redistribution of electron density among the reactant partners. Accordingly acid-base and redox reactions form cardinal components in all branches of chemistry, e.g., inorganic, organic, physical or biochemistry. That is the reason it forms an integral part of the undergraduate curriculum all throughout the globe. In an electronegativity (χ)- hardness (η) landscape diagram the diagonal χ = η line separates reducing agents from oxidizing agents as well as Lewis acids from Lewis bases. While electronegativity is related to the degree of electron transfer between two reactants, hardness is related to the resistance to that process. Accordingly the electronegativities of oxidizing agents/Lewis acids are generally greater than the corresponding hardness values and the reverse is true for reducing agents/Lewis bases. Electrophiles and nucleophiles are also expected to follow similar trends.

  15. Evidence that human Fc gamma receptor IIA (CD32) subtypes are not receptors for oxidized LDL.

    PubMed

    Morganelli, P M; Groveman, D S; Pfeiffer, J R

    1997-11-01

    Several lines of evidence suggest that clearance of oxidized LDL (oxLDL) immune complexes by macrophage IgG Fc receptors (Fc gamma Rs) plays a role in atherogenesis. Ox-LDL may also be cleared directly by Fc gamma Rs, as shown for murine Fc gamma RII-B2. In humans, the homologous Fc gamma R is Fc gamma RIIA (CD32), which is abundantly expressed on monocytes and macrophages and shares 60% sequence identity with murine Fc gamma RII-B2. As murine Fc gamma RII-B2 and human Fc gamma RIIA also share similar IgG ligand-binding properties, the purpose of this study was to test the hypothesis that human CD32 is a receptor for oxLDL. For these studies we used transfected Chinese hamster ovary (CHO) cells, monocytes, and cell lines that functionally express either of two Fc gamma RIIA subtypes (R131 or H131) and assayed binding or degradation of several preparations of oxLDL. The integrity of all oxLDL preparations was checked by studying their ability to react with CHO cells expressing human type I scavenger receptors and by other characteristics of lipoprotein oxidation. Although we showed that each preparation of oxLDL could recognize class A or class B scavenger receptors, we did not detect any differences in the binding or degradation of any type of oxLDL preparation among control versus CHO cell transfectants. Using monocytes that express Fc gamma RIIA and CD36, we showed that the binding of oxLDL was inhibited by antibodies to CD36, but not by Fc gamma RIIA antibodies. Thus, the data do not support the hypothesis that human Fc gamma RIIA is by itself a receptor for oxLDL. We conclude that human CD32 can mediate uptake of lipoprotein immune complexes, but does not mediate uptake of oxLDL in the absence of anti-oxLDL antibodies. OxLDL may interact with human mononuclear phagocytes directly via other types of receptors, such as class A and class B scavenger receptors or CD68.

  16. Effect of Electronegativity on Bipolar Resistive Switching in a WO3-Based Asymmetric Capacitor Structure.

    PubMed

    Kim, Jongmin; Inamdar, Akbar I; Jo, Yongcheol; Woo, Hyeonseok; Cho, Sangeun; Pawar, Sambhaji M; Kim, Hyungsang; Im, Hyunsik

    2016-04-13

    This study investigates the transport and switching time of nonvolatile tungsten oxide based resistive-switching (RS) memory devices. These devices consist of a highly resistive tungsten oxide film sandwiched between metal electrodes, and their RS characteristics are bipolar in the counterclockwise direction. The switching voltage, retention, endurance, and switching time are strongly dependent on the type of electrodes used, and we also find quantitative and qualitative evidence that the electronegativity (χ) of the electrodes plays a key role in determining the RS properties and switching time. We also propose an RS model based on the role of the electronegativity at the interface.

  17. Clinically used selective oestrogen receptor modulators increase LDL receptor activity in primary human lymphocytes

    PubMed Central

    Cerrato, F; Fernández-Suárez, M E; Alonso, R; Alonso, M; Vázquez, C; Pastor, O; Mata, P; Lasunción, M A; Gómez-Coronado, D

    2015-01-01

    Background and Purpose Treatment with selective oestrogen receptor modulators (SERMs) reduces low-density lipoprotein (LDL) cholesterol levels. We assessed the effect of tamoxifen, raloxifene and toremifene and their combinations with lovastatin on LDL receptor activity in lymphocytes from normolipidaemic and familial hypercholesterolaemic (FH) subjects, and human HepG2 hepatocytes and MOLT-4 lymphoblasts. Experimental Approach Lymphocytes were isolated from peripheral blood, treated with different compounds, and 1,1′-dioctadecyl-3,3,3,3′-tetramethylindocarbocyanine perchlorate (DiI)-labelled LDL uptake was analysed by flow cytometry. Key Results Tamoxifen, toremifene and raloxifene, in this order, stimulated DiI-LDL uptake by lymphocytes by inhibiting LDL-derived cholesterol trafficking and subsequent down-regulation of LDL receptor expression. Differently to what occurred in HepG2 and MOLT-4 cells, only tamoxifen consistently displayed a potentiating effect with lovastatin in primary lymphocytes. The SERM-mediated increase in LDL receptor activity was not altered by the anti-oestrogen ICI 182 780 nor was it reproduced by 17β-oestradiol. However, the tamoxifen-active metabolite endoxifen was equally effective as tamoxifen. The SERMs produced similar effects on LDL receptor activity in heterozygous FH lymphocytes as in normal lymphocytes, although none of them had a potentiating effect with lovastatin in heterozygous FH lymphocytes. The SERMs had no effect in homozygous FH lymphocytes. Conclusions and Implications Clinically used SERMs up-regulate LDL receptors in primary human lymphocytes. There is a mild enhancement between SERMs and lovastatin of lymphocyte LDLR activity, the potentiation being greater in HepG2 and MOLT-4 cells. The effect of SERMs is independent of oestrogen receptors but is preserved in the tamoxifen-active metabolite endoxifen. This mechanism may contribute to the cholesterol-lowering action of SERMs. PMID:25395200

  18. HDL (Good), LDL (Bad) Cholesterol and Triglycerides

    MedlinePlus

    ... and proteins. These are called – no big surprise – lipoproteins. Two types of lipoproteins carry cholesterol to and from cells. One is low-density lipoprotein, or LDL. The other is high-density lipoprotein, ...

  19. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization

    PubMed Central

    Grosheva, Inna; Haka, Abigail S.; Qin, Chunbo; Pierini, Lynda M.; Maxfield, Frederick R.

    2009-01-01

    Objective Interaction of macrophages with aggregated matrix-anchored lipoprotein deposits is an important initial step in atherogenesis. Aggregated lipoproteins require different cellular uptake processes than those used for endocytosis of monomeric lipoproteins. In this study, we tested the hypothesis that engagement of aggregated LDL (agLDL) by macrophages could lead to local increases in free cholesterol levels and that these increases in free cholesterol regulate signals that control cellular actin. Methods and Results AgLDL resides for prolonged periods in surface-connected compartments. While agLDL is still extracellular, we demonstrate that an increase in free cholesterol occurs at sites of contact between agLDL and cells due to hydrolysis of agLDL-derived cholesteryl ester. This increase in free cholesterol causes enhanced actin polymerization around the agLDL. Inhibition of cholesteryl ester hydrolysis results in decreased actin polymerization. Conclusions We describe a novel process that occurs during agLDL-macrophage interactions in which local release of free cholesterol causes local actin polymerization, promoting a pathologic positive feedback loop for increased catabolism of agLDL and eventual foam cell formation. PMID:19556523

  20. Aggregated LDL in contact with macrophages induces local increases in free cholesterol levels that regulate local actin polymerization.

    PubMed

    Grosheva, Inna; Haka, Abigail S; Qin, Chunbo; Pierini, Lynda M; Maxfield, Frederick R

    2009-10-01

    Interaction of macrophages with aggregated matrix-anchored lipoprotein deposits is an important initial step in atherogenesis. Aggregated lipoproteins require different cellular uptake processes than those used for endocytosis of monomeric lipoproteins. In this study, we tested the hypothesis that engagement of aggregated LDL (agLDL) by macrophages could lead to local increases in free cholesterol levels and that these increases in free cholesterol regulate signals that control cellular actin. AgLDL resides for prolonged periods in surface-connected compartments. Although agLDL is still extracellular, we demonstrate that an increase in free cholesterol occurs at sites of contact between agLDL and cells because of hydrolysis of agLDL-derived cholesteryl ester. This increase in free cholesterol causes enhanced actin polymerization around the agLDL. Inhibition of cholesteryl ester hydrolysis results in decreased actin polymerization. We describe a novel process that occurs during agLDL-macrophage interactions in which local release of free cholesterol causes local actin polymerization, promoting a pathological positive feedback loop for increased catabolism of agLDL and eventual foam cell formation.

  1. MCP-1 binds to oxidized LDL and is carried by lipoprotein(a) in human plasma

    PubMed Central

    Wiesner, Philipp; Tafelmeier, Maria; Chittka, Dominik; Choi, Soo-Ho; Zhang, Li; Byun, Young Sup; Almazan, Felicidad; Yang, Xiaohong; Iqbal, Navaid; Chowdhury, Punam; Maisel, Alan; Witztum, Joseph L.; Handel, Tracy M.; Tsimikas, Sotirios; Miller, Yury I.

    2013-01-01

    Lipoprotein oxidation plays an important role in pathogenesis of atherosclerosis. Oxidized low density lipoprotein (OxLDL) induces profound inflammatory responses in vascular cells, such as production of monocyte chemoattractant protein-1 (MCP-1) [chemokine (C-C motif) ligand 2], a key chemokine in the initiation and progression of vascular inflammation. Here we demonstrate that OxLDL also binds MCP-1 and that the OxLDL-bound MCP-1 retains its ability to recruit monocytes. A human MCP-1 mutant in which basic amino acids Arg-18 and Lys-19 were replaced with Ala did not bind to OxLDL. The MCP-1 binding to OxLDL was inhibited by the monoclonal antibody E06, which binds oxidized phospholipids (OxPLs) in OxLDL. Because OxPLs are carried by lipoprotein(a) [Lp(a)] in human plasma, we tested to determine whether Lp(a) binds MCP-1. Recombinant wild-type but not mutant MCP-1 added to human plasma bound to Lp(a), and its binding was inhibited by E06. Lp(a) captured from human plasma contained MCP-1 and the Lp(a)-associated endogenous MCP-1 induced monocyte migration. These results demonstrate that OxLDL and Lp(a) bind MCP-1 in vitro and in vivo and that OxPLs are major determinants of the MCP-1 binding. The association of MCP-1 with OxLDL and Lp(a) may play a role in modulating monocyte trafficking during atherogenesis. PMID:23667177

  2. Effect of natriuretic peptide family on the oxidized LDL-induced migration of human coronary artery smooth muscle cells.

    PubMed

    Kohno, M; Yokokawa, K; Yasunari, K; Kano, H; Minami, M; Ueda, M; Yoshikawa, J

    1997-10-01

    The migration of medial smooth muscle cells (SMCs) into the intima is proposed to be an important process of intimal thickening in atherosclerotic lesions. The present study examined the possible effect of a novel endothelium-derived relaxing peptide, C-type natriuretic peptide (CNP), on oxidized low-density lipoprotein (LDL)-induced migration of cultured human coronary artery SMCs by the Boyden's chamber method. The effect of CNP was compared with that of atrial and brain natriuretic peptides (ANP and BNP, respectively). Oxidized LDL stimulates SMC migration in a concentration-dependent manner between 20 and 200 micrograms/mL. This stimulation was chemotactic in nature but was not chemokinetic. By contrast, native LDL was without significant activity. CNP-22 clearly inhibited SMC migration stimulated with 200 micrograms/mL oxidized LDL in a concentration-dependent manner between 10(-9) and 10(-6) mol/L. ANP-(1-28) and BNP-32 also inhibited oxidized LDL-induced SMC migration at concentrations of 10(-7) and 10(-6) mol/L, but these effects were weaker than the effect of CNP-22. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. Oxidized LDL-induced migration was significantly inhibited by a stable analogue of cGMP, 8-bromo-cGMP, or an activator of the cytosolic guanylate cyclase, sodium nitroprusside. These natriuretic peptides did not suppress the cell adhesion either in the absence or presence of oxidized LDL. These data indicate that oxidized LDL stimulates migration of human coronary artery SMCs and that natriuretic peptides, especially CNP, inhibit this stimulated SMC migration, at least in part, through a cGMP-dependent process. Taken together with the finding that oxidized LDL is present in the intima, CNP may play a role as a local antimigration factor during the process of intimal thickening in hypercholesterolemia-induced coronary atherosclerosis.

  3. Complex transition metal hydrides: linear correlation of countercation electronegativity versus T-D bond lengths.

    PubMed

    Humphries, T D; Sheppard, D A; Buckley, C E

    2015-06-30

    For homoleptic 18-electron complex hydrides, an inverse linear correlation has been established between the T-deuterium bond length (T = Fe, Co, Ni) and the average electronegativity of the metal countercations. This relationship can be further employed towards aiding structural solutions and predicting physical properties of novel complex transition metal hydrides.

  4. Relating polarizability to volume, ionization energy, electronegativity, hardness, moments of momentum, and other molecular properties

    SciTech Connect

    Blair, Shamus A.; Thakkar, Ajit J.

    2014-08-21

    Semiquantitative relationships between the mean static dipole polarizability and other molecular properties such as the volume, ionization energy, electronegativity, hardness, and moments of momentum are explored. The relationships are tested using density functional theory computations on the 1641 neutral, ground-state, organic molecules in the TABS database. The best polarizability approximations have median errors under 5%.

  5. A new method to derive electronegativity from resonant inelastic x-ray scattering

    SciTech Connect

    Carniato, S.; Journel, L.; Guillemin, R.; Piancastelli, M. N.; Simon, M.; Stolte, W. C.; Lindle, D. W.

    2012-10-14

    Electronegativity is a well-known property of atoms and substituent groups. Because there is no direct way to measure it, establishing a useful scale for electronegativity often entails correlating it to another chemical parameter; a wide variety of methods have been proposed over the past 80 years to do just that. This work reports a new approach that connects electronegativity to a spectroscopic parameter derived from resonant inelastic x-ray scattering. The new method is demonstrated using a series of chlorine-containing compounds, focusing on the Cl 2p{sup -1}LUMO{sup 1} electronic states reached after Cl 1s{yields} LUMO core excitation and subsequent KL radiative decay. Based on an electron-density analysis of the LUMOs, the relative weights of the Cl 2p{sub z} atomic orbital contributing to the Cl 2p{sub 3/2} molecular spin-orbit components are shown to yield a linear electronegativity scale consistent with previous approaches.

  6. Electronegativity effects and single covalent bond lengths of molecules in the gas phase.

    PubMed

    Lang, Peter F; Smith, Barry C

    2014-06-07

    This paper discusses in detail the calculation of internuclear distances of heteronuclear single bond covalent molecules in the gaseous state. It reviews briefly the effect of electronegativity in covalent bond length. A set of single bond covalent radii and electronegativity values are proposed. Covalent bond lengths calculated by an adapted form of a simple expression (which calculated internuclear separation of different Group 1 and Group 2 crystalline salts to a remarkable degree of accuracy) show very good agreement with observed values. A small number of bond lengths with double bonds as well as bond lengths in the crystalline state are calculated using the same expression and when compared with observed values also give good agreement. This work shows that covalent radii are not additive and that radii in the crystalline state are different from those in the gaseous state. The results also show that electronegativity is a major influence on covalent bond lengths and the set of electronegativity scale and covalent radii proposed in this work can be used to calculate covalent bond lengths in different environments that have not yet been experimentally measured.

  7. Electron density measurements in very electronegative plasmas using different diagnostic techniques: theory and experiments

    NASA Astrophysics Data System (ADS)

    Rafalskyi, Dmytro; Lafleur, Trevor; Aanesland, Ane

    2016-09-01

    Very electronegative plasmas (known as ``ion-ion'' plasmas) are used in different applications including material processing, space propulsion and thermonuclear fusion. Diagnostics of ion-ion plasmas can be performed using different probe techniques, including Langmuir and hairpin probes, RF, microwave and optical diagnostics. However, in certain applications (for example, in the electronegative thruster PEGASES), the electron density is too low (<1012m-3) to be reliably measured by these standard techniques. This is further complicated by the presence of strong, non-homogeneous, magnetic fields in the plasma ( 200 G) and the relatively small plasma size (few cm). In this work we compare results achieved with a Langmuir probe, and with an independent measurement of the electron density using a matched dipole probe. Measurements are performed in an SF6 plasma with an electronegativity in the range between a few hundred to a few thousand. We show here that though the model itself can correctly describe the plasma-probe interactions, there is a critical value of plasma electronegativity above which the electron density measured with a Langmuir probe can give only an upper limit estimation.

  8. Coincubation of PON1, APO A1, and LCAT increases the time HDL is able to prevent LDL oxidation.

    PubMed

    Hine, David; Mackness, Bharti; Mackness, Mike

    2012-02-01

    The inhibition of low-density lipoprotein (LDL) oxidation by high-density lipoprotein (HDL) is a major antiatherogenic property of this lipoprotein. This activity is due, in part, to HDL associated proteins. However, whether these proteins interact in the antioxidant activity of HDL is unknown. LDL was incubated with apolipoprotein A1 (apo A1), lecithin:cholesterol acyltransferase (LCAT), and paraoxonase-1 (PON1) alone or in combination, in the presence or absence of HDL under oxidizing conditions. LDL lipid peroxide concentrations were determined. Apo A1, LCAT, and PON1 all inhibit LDL oxidation in the absence of HDL and enhance the ability of HDL to inhibit LDL oxidation. Their effect was additive rather than synergistic; the combination of these proteins significantly enhanced the length of time LDL was protected from oxidation. This seemed to be due to the ability of PON1 to prevent the oxidative inactivation of LCAT. Apo A1, LCAT, and PON1 can all contribute to the antioxidant activity of HDL in vitro. The combination of apo A1, LCAT, and PON1 prolongs the time that HDL can prevent LDL oxidation, due, at least in part, to the prevention LCAT inactivation.

  9. Effect of fish oil supplementation on serum triglycerides, LDL cholesterol and LDL subfractions in hypertriglyceridemic adults.

    PubMed

    Oelrich, B; Dewell, A; Gardner, C D

    2013-04-01

    The well-established triglyceride (TG) lowering effect of fish oil is accompanied by an increase in LDL-cholesterol (LDL-C) concentration. Less is known about the differential impact on LDL particle distribution - the smaller particles being associated with a greater risk for atherosclerosis. We aimed to examine the changes in serum concentrations of four subclasses of LDL particles as well as shifts in LDL phenotype patterns (A, B, AB) among hypertriglyceridemic adults. This was a secondary analysis from a double-blind, parallel design, placebo controlled trial with 42 adults that experienced significant TG lowering and modest increases in total LDL-C concentrations after 12 weeks of 4 g/d EPA + DHA. Reduction in serum TG concentrations (mean ± SEM) was -26 ± 4% (-0.81 ± 10.12 mmol/L), p < 0.0001. Total LDL-C concentration increased by 13 ± 3% (+0.31 ± 0.08 mmol/L), p < 0.0001. The 12-week changes in concentrations of LDL1, LDL2, LDL3 and LDL4 were +0.06 ± 0.02 mmol/L [+2.2 ± 0.7 mg/dL], +0.07 ± 0.03 mmol/L [+2.6 ± 1.0 mg/dL], +0.16 ± 0.05 mmol/L [+6.3 ± 1.8 mg/dL], and +0.04 ± 0.04 mmol/L [+1.4 ± 1.7 mg/dL], respectively (+20 ± 5%, +64 ± 13%, +26 ± 6%, and +17 ± 9%), p < 0.05 for all but LDL4. Changes in LDL phenotype patterns A, B and A/B were negligible and not statistically significant. In this population of hypertriglyceridemic adults, dietary supplementation with fish oil resulted in an increase in total LDL-C concentration which was distributed relatively evenly across the range of smaller and more atherogenic as well as larger and less atherogenic LDL particles. Copyright © 2011. Published by Elsevier B.V.

  10. Inhibition of the aryl hydrocarbon receptor prevents Western diet-induced obesity. Model for AHR activation by kynurenine via oxidized-LDL, TLR2/4, TGFβ, and IDO1.

    PubMed

    Moyer, Benjamin J; Rojas, Itzel Y; Kerley-Hamilton, Joanna S; Hazlett, Haley F; Nemani, Krishnamurthy V; Trask, Heidi W; West, Rachel J; Lupien, Leslie E; Collins, Alan J; Ringelberg, Carol S; Gimi, Barjor; Kinlaw, William B; Tomlinson, Craig R

    2016-06-01

    Obesity is an increasingly urgent global problem, yet, little is known about its causes and less is known how obesity can be effectively treated. We showed previously that the aryl hydrocarbon receptor (AHR) plays a role in the regulation of body mass in mice fed Western diet. The AHR is a ligand-activated nuclear receptor that regulates genes involved in a number of biological pathways, including xenobiotic metabolism and T cell polarization. This study was an investigation into whether inhibition of the AHR prevents Western diet-based obesity. Male C57Bl/6J mice were fed control and Western diets with and without the AHR antagonist α-naphthoflavone or CH-223191, and a mouse hepatocyte cell line was used to delineate relevant cellular pathways. Studies are presented showing that the AHR antagonists α-naphthoflavone and CH-223191 significantly reduce obesity and adiposity and ameliorates liver steatosis in male C57Bl/6J mice fed a Western diet. Mice deficient in the tryptophan metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) were also resistant to obesity. Using an AHR-directed, luciferase-expressing mouse hepatocyte cell line, we show that the transforming growth factor β1 (TGFβ1) signaling pathway via PI3K and NF-κB and the toll-like receptor 2/4 (TLR2/4) signaling pathway stimulated by oxidized low-density lipoproteins via NF-κB, each induce luciferase expression; however, TLR2/4 signaling was significantly reduced by inhibition of IDO1. At physiological levels, kynurenine but not kynurenic acid (both tryptophan metabolites and known AHR agonists) activated AHR-directed luciferase expression. We propose a hepatocyte-based model, in which kynurenine production is increased by enhanced IDO1 activity stimulated by TGFβ1 and TLR2/4 signaling, via PI3K and NF-κB, to perpetuate a cycle of AHR activation to cause obesity; and inhibition of the AHR, in turn, blocks the cycle's output to prevent obesity. The AHR with its broad ligand binding specificity

  11. A PCSK9-binding antibody that structurally mimics the EGF(A) domain of LDL-receptor reduces LDL cholesterol in vivo.

    PubMed

    Ni, Yan G; Di Marco, Stefania; Condra, Jon H; Peterson, Laurence B; Wang, Weirong; Wang, Fubao; Pandit, Shilpa; Hammond, Holly A; Rosa, Ray; Cummings, Richard T; Wood, Dana D; Liu, Xiaomei; Bottomley, Matthew J; Shen, Xun; Cubbon, Rose M; Wang, Sheng-ping; Johns, Douglas G; Volpari, Cinzia; Hamuro, Lora; Chin, Jayne; Huang, Lingyi; Zhao, Jing Zhang; Vitelli, Salvatore; Haytko, Peter; Wisniewski, Douglas; Mitnaul, Lyndon J; Sparrow, Carl P; Hubbard, Brian; Carfí, Andrea; Sitlani, Ayesha

    2011-01-01

    Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) regulates LDL cholesterol levels by inhibiting LDL receptor (LDLr)-mediated cellular LDL uptake. We have identified a fragment antigen-binding (Fab) 1D05 which binds PCSK9 with nanomolar affinity. The fully human antibody 1D05-IgG2 completely blocks the inhibitory effects of wild-type PCSK9 and two gain-of-function human PCSK9 mutants, S127R and D374Y. The crystal structure of 1D05-Fab bound to PCSK9 reveals that 1D05-Fab binds to an epitope on the PCSK9 catalytic domain which includes the entire LDLr EGF(A) binding site. Notably, the 1D05-Fab CDR-H3 and CDR-H2 loops structurally mimic the EGF(A) domain of LDLr. In a transgenic mouse model (CETP/LDLr-hemi), in which plasma lipid and PCSK9 profiles are comparable to those of humans, 1D05-IgG2 reduces plasma LDL cholesterol to 40% and raises hepatic LDLr protein levels approximately fivefold. Similarly, in healthy rhesus monkeys, 1D05-IgG2 effectively reduced LDL cholesterol 20%-50% for over 2 weeks, despite its relatively short terminal half-life (t(1/2) = 3.2 days). Importantly, the decrease in circulating LDL cholesterol corresponds closely to the reduction in free PCSK9 levels. Together these results clearly demonstrate that the LDL-lowering effect of the neutralizing anti-PCSK9 1D05-IgG2 antibody is mediated by reducing the amount of PCSK9 that can bind to the LDLr.

  12. Enhancing the low frequency THz resonances (< 1 THz) of organic molecules via electronegative atom substitution

    NASA Astrophysics Data System (ADS)

    Dash, Jyotirmayee; Ray, Shaumik; Pesala, Bala

    2015-03-01

    Terahertz (THz) technology is an active area of research with various applications in non-intrusive imaging and spectroscopy. Very few organic molecules have significant resonances below 1 THz. Understanding the origin of low frequency THz modes in these molecules and their absence in other molecules could be extremely important in design and engineering molecules with low frequency THz resonances. These engineered molecules can be used as THz tags for anti-counterfeiting applications. Studies show that low frequency THz resonances are commonly observed in molecules having higher molecular mass and weak intermolecular hydrogen bonds. In this paper, we have explored the possibility of enhancing the strength of THz resonances below 1 THz through electronegative atom substitution. Adding an electronegative atom helps in achieving higher hydrogen bond strength to enhance the resonances below 1 THz. Here acetanilide has been used as a model system. THz-Time Domain Spectroscopy (THz-TDS) results show that acetanilide has a small peak observed below 1 THz. Acetanilide can be converted to 2-fluoroacetanilide by adding an electronegative atom, fluorine, which doesn't have any prominent peak below 1 THz. However, by optimally choosing the position of the electronegative atom as in 4-fluoroacetanilide, a significant THz resonance at 0.86 THz is observed. The origin of low frequency resonances can be understood by carrying out Density Functional Theory (DFT) simulations of full crystal structure. These studies show that adding an electronegative atom to the organic molecules at an optimized position can result in significantly enhanced resonances below 1 THz.

  13. Accumulation of "small dense" low density lipoproteins (LDL) in a homozygous patients with familial defective apolipoprotein B-100 results from heterogenous interaction of LDL subfractions with the LDL receptor.

    PubMed Central

    März, W; Baumstark, M W; Scharnagl, H; Ruzicka, V; Buxbaum, S; Herwig, J; Pohl, T; Russ, A; Schaaf, L; Berg, A

    1993-01-01

    The interaction of LDL and LDL subfractions from a patient homozygous for familial defective apoB-100 (FDB) has been studied. His LDL cholesterol ranged from 2.65 to 3.34 g/liter. In cultured fibroblasts, binding, internalization, and degradation of the patient's LDL was diminished, but not completely abolished. The patient's apolipoprotein E concentration was low, and the amount of apolipoprotein E associated with LDL was not elevated over normal. LDL were separated into six subfractions: LDL-1 (1.019-1.031 kg/liter), LDL-2 (1.031-1.034 kg/liter), LDL-3 (1.034-1.037 kg/liter), LDL-4 (1.037-1.040 kg/liter), LDL-5 (1.040-1.044 kg/liter), and LDL-6 (> 1.044 kg/liter). LDL-5 and LDL-6 selectively accumulated in the patient's plasma. Concentrations of LDL-1 to 3 were normal. The LDL receptor-mediated uptake of LDL-1 and LDL-2 could not be distinguished from normal LDL. LDL-3 and LDL-4 displayed reduced uptake; LDL-5 and LDL-6 were completely defective in binding. When apolipoprotein E-containing particles were removed by immunoabsorption before preparing subfractions, LDL-3 and LDL-4, but not LDL-1 and LDL-2, retained some receptor binding activity. We conclude that in FDB, LDL-1 and LDL-2 contain sufficient apolipoprotein E to warrant normal cellular uptake. In LDL-3 and LDL-4, the defective apoB-100 itself displays some receptor binding; LDL-5 and LDL-6 are inable to interact with LDL receptors and accumulate in plasma. Images PMID:8254047

  14. Biological activity of some naturally occurring resins, gums and pigments against in vitro LDL oxidation.

    PubMed

    Andrikopoulos, Nikolaos K; Kaliora, Andriana C; Assimopoulou, Andreana N; Papapeorgiou, Vassilios P

    2003-05-01

    Naturally occurring gums and resins with beneficial pharmaceutical and nutraceutical properties were tested for their possible protective effect against copper-induced LDL oxidation in vitro. Chiosmastic gum (CMG) (Pistacia lentiscus var. Chia resin) was the most effective in protecting human LDL from oxidation. The minimum and maximum doses for the saturation phenomena of inhibition of LDL oxidation were 2.5 mg and 50 mg CMG (75.3% and 99.9%, respectively). The methanol/water extract of CMG was the most effective compared with other solvent combinations. CMG when fractionated in order to determine a structure-activity relationship showed that the total mastic essential oil, collofonium-like residue and acidic fractions of CMG exhibited a high protective activity ranging from 65.0% to 77.8%. The other natural gums and resins (CMG resin 'liquid collection', P. terebinthus var. Chia resin, dammar resin, acacia gum, tragacanth gum, storax gum) also tested as above, showed 27.0%-78.8% of the maximum LDL protection. The other naturally occurring substances, i.e. triterpenes (amyrin, oleanolic acid, ursolic acid, lupeol, 18-a-glycyrrhetinic acid) and hydroxynaphthoquinones (naphthazarin, shikonin and alkannin) showed 53.5%-78.8% and 27.0%-64.1% LDL protective activity, respectively. The combination effects (68.7%-76.2% LDL protection) of ursolic-, oleanolic- and ursodeoxycholic- acids were almost equal to the effect (75.3%) of the CMG extract in comparable doses.

  15. Minimally Modified LDL Upregulates Endothelin Type A Receptors in Rat Coronary Arterial Smooth Muscle Cells

    PubMed Central

    Li, Jie; Cao, Lei; Xu, Cang-Bao; Wang, Jun-Jie

    2013-01-01

    Minimally modified low-density lipoprotein (mmLDL) is a risk factor for cardiovascular disease. The present study investigated the effects of mmLDL on the expression of endothelin type A (ETA) receptors in coronary arteries. Rat coronary arteries were organ-cultured for 24 h. The contractile responses were recorded using a myographic system. ETA receptor mRNA and protein expressions were determined using real-time PCR and western blotting, respectively. The results showed that organ-culturing in the presence of mmLDL enhanced the arterial contractility mediated by the ETA receptor in a concentration-dependent and time-dependent manner. Culturing with mmLDL (10 μg/mL) for 24 h shifted the concentration-contractile curves toward the left significantly with increased Emax of 228% ± 20% from control of 100% ± 10% and significantly increased ETA receptor mRNA and protein levels. Inhibition of the protein kinase C, extracellular signal-related kinases 1 and 2 (ERK1/2), or NF-κB activities significantly attenuated the effects of mmLDL. The c-Jun N-terminal kinase inhibitor or the p38 pathway inhibitor, however, had no such effects. The results indicate that mmLDL upregulates the ETA receptors in rat coronary arterial smooth muscle cells mainly via activating protein kinase C, ERK1/2, and the downstream transcriptional factor, NF-κB. PMID:23861561

  16. Baicalein protects against oxLDL-caused oxidative stress and inflammation by modulation of AMPK- alpha

    PubMed Central

    Chan, Shih-Hung; Shih, Jhih-Yuan; Cheng, Yung-Hsin; Tsai, Yi-Ju; Lin, Huei-Chen; Chu, Pei-Ming

    2016-01-01

    Atherosclerosis is considered to be a form of chronic inflammation and a disorder of lipid metabolism. Oxidative transformations in the lipid and apolipoprotein B (Apo B) constituent of low density lipoprotein drive the initial step in atherogenesis due to macrophage scavenger receptors identify oxidized LDL (oxLDL) but non-oxidized LDL. The human vascular endothelial cells fact a critical role in vasodilation, provides a nonadhesive surface for circulation, reduces vascular smooth muscle proliferation, inflammation, thrombus formation and platelet aggregation. Assembly of oxLDL contribute to stimulation of endothelial cells with up-regulation of adhesion molecules, increase oxidative stress to the vascular endothelium and inhibition of NO-mediated vasodilation. When adhesion molecules are over-expressed on the surface of endothelial cells under oxLDL stimulation, it will recruit monocytes to the arterial wall. Then adherent monocytes will migrate into the subendothelial space and subsequently differentiate into macrophages. In the subendothelial space, oxLDL will be taken up by macrophages, thereby causing the substantial cholesterol accumulation and the foam cells production. PMID:27776344

  17. Protein modification elicited by oxidized low-density lipoprotein (LDL) in endothelial cells: protection by (-)-epicatechin.

    PubMed

    Steffen, Yvonne; Jung, Tobias; Klotz, Lars-Oliver; Schewe, Tankred; Grune, Tilman; Sies, Helmut

    2007-04-01

    The action of oxidatively modified low-density lipoprotein (oxLDL) on vascular endothelial cells has been proposed to be a crucial process leading to endothelial dysfunction and atherogenesis. OxLDL was shown here to elicit oxidative stress in bovine aortic endothelial cells or human umbilical vein endothelial cells, as judged by an increase in 2',7'-dichlorofluorescein fluorescence and elevated levels of carbonylated, nitrated, and 2-hydroxynonenal-coupled proteins. These effects were sensitive to apocynin, indicating involvement of NADPH oxidase. A 170-kDa polypeptide carbonylated upon exposure of cells to oxLDL was identified by immunoprecipitation as EGF receptor. Immunocytochemical visualization by confocal microscopy revealed the highest levels of modified proteins in the perinuclear region. Exposure of endothelial cells to oxLDL led to modulation of the expression levels of *NO synthases; the endothelial isoform (eNOS) was down-regulated via proteasomal degradation, whereas the inducible isoform (iNOS) was up-regulated in an enzymatically active state. eNOS protein was found to be both carbonylated and nitrated upon exposure of cells to oxLDL. iNOS contributed to the generation of modified proteins as judged by the effects of the selective inhibitor L-NIO. These oxLDL-elicited changes in vascular endothelial cells described were suppressed by (-)-epicatechin, a dietary polyphenol, which inhibited NADPH oxidase activity in these cells.

  18. Oxidized LDL enhances stretch-induced smooth muscle cell proliferation through alterations in nuclear protein import.

    PubMed

    Chahine, Mirna N; Dibrov, Elena; Blackwood, David P; Pierce, Grant N

    2012-12-01

    Mechanical stress contributes to hypertension and atherosclerosis partly through the stimulation of vascular smooth muscle cell (VSMC) proliferation. Oxidized low density lipoprotein (oxLDL) is another important atherogenic factor that can increase VSMC proliferation. The purpose of this study was to investigate whether oxLDL could further enhance the proliferative action of mechanical stretch on VSMC, and to determine the mechanism responsible for this interaction. Because nuclear protein import is critical in regulating gene expression, transcription, and cell proliferation, its involvement in the mitogenic effects of oxLDL and mechanical stress was studied. OxLDL enhanced the proliferative effects of mechanical stretch on its own in rabbit aortic VSMC, and induced increases in the expression of HSP60 in an additive manner. Adenoviral-mediated overexpression of HSP60 induced increases in cell proliferation compared with uninfected VSMC. Mechanical stretch and oxLDL stimulated the rate of nuclear protein import in VSMC and increased the expression of nucleoporins. These effects were sensitive to inhibition of the MAPK pathway. We conclude that oxLDL and mechanical stretch have a synergistic effect on VSMC proliferation. This synergistic effect is induced through a stimulation of nuclear protein import via HSP60 and an activation of the MAPK pathway.

  19. F(ab')2 fragments of anti-oxidized LDL IgG attenuate vascular inflammation and atherogenesis in diabetic LDL receptor-deficient mice.

    PubMed

    Li, Yanchun; Lu, Zhongyang; Huang, Yan; Lopes-Virella, Maria F; Virella, Gabriel

    2016-12-01

    Considerable evidence is available supporting the atherogenic role of immune complexes (IC) formed by modified forms of LDL and their corresponding antibodies in humans and other species. In this study, we assessed the effect of IgG F(ab')2 fragments of murine anti-mouse oxLDL, which binds oxLDL forming IC that cannot interact with Fcγ receptors, on the development of atherosclerosis in diabetic LDL receptor-deficient (LDLR-/-) mice. Immunohistochemical study showed that treatment with the F(ab')2 fragments for 8weeks significantly reduced the content of macrophages and interleukin 6 expression in atherosclerotic lesions. Furthermore, histological study showed that treatment with the same F(ab')2 fragments significantly reduced atherosclerotic lesions in diabetic LDLR-/- mice. Taken together, this study demonstrated for the first time that F(ab')2 fragments of anti-oxLDL IgG inhibited vascular inflammation and atherogenesis in diabetic LDLR-/- mice and uncovered a possible new avenue for therapy in patients at high risk to progress to cardiovascular complications. Copyright © 2016. Published by Elsevier Inc.

  20. Inhibitory effect of Piper betel leaf extracts on copper-mediated LDL oxidation and oxLDL-induced lipid accumulation via inducing reverse cholesterol transport in macrophages.

    PubMed

    Ma, Gwo-Chin; Wu, Pei-Fang; Tseng, Hsien-Chun; Chyau, Charng-Cherng; Lu, Hsiu-Chin; Chou, Fen-Pi

    2013-12-15

    Piper betel leaf (PBL) has the biological capabilities of detoxification and can work as an anti-inflammatory agent and an anti-oxidant. In this study, we evaluated the anti-oxidative activity of the extract of Piper betel leaves (PBLs) on the basis of Cu(2+)-mediated oxidation, and its ability to prevent foam cell formation in a model for oxidised low density lipoprotein (oxLDL)-induced lipid accumulation in macrophages. Our data demonstrated that PBLs were able to inhibit LDL oxidation in vitro and are able to reduce the lipid accumulation in macrophages. We showed the underlying mechanisms to be the following: PBLs up-regulated the protein levels of the class A and class B scavenger receptors, the membrane lipid transporter ABCA1, and its upstream regulator Liver X receptor (LXR) in the macrophages exposed to oxLDL. The results suggested that PBLs activated the reverse cholesterol transport mechanism to enhance the metabolism of the oxLDL that could prevent both lipid accumulation and foam cell formation and further minimise the possible damage of vessels caused by the oxLDL. Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. LDL Particle Number and Risk of Future Cardiovascular Disease in the Framingham Offspring Study – Implications for LDL Management

    PubMed Central

    Cromwell, William C.; Otvos, James D.; Keyes, Michelle J.; Pencina, Michael J.; Sullivan, Lisa; Vasan, Ramachandran S.; Wilson, Peter W.F.; D’Agostino, Ralph B.

    2009-01-01

    Background The cholesterol content of LDL particles is variable, causing frequent discrepancies between concentrations of LDL cholesterol and LDL particle number. In managing patients at risk for cardiovascular disease (CVD) to LDL target levels, it is unclear whether LDL cholesterol provides the optimum measure of residual risk and adequacy of LDL lowering treatment. Objective To compare the ability of alternative measures of LDL to provide CVD risk discrimination at relatively low levels consistent with current therapeutic targets. Methods Concentrations of LDL cholesterol (LDL-C) and non-HDL cholesterol (non-HDL-C) were measured chemically and LDL particle number (LDL-P) and VLDL particle number (VLDL-P) were measured by nuclear magnetic resonance (NMR) in 3066 middle-aged white participants (53% women) without CVD in the Framingham Offspring cohort. The main outcome measure was incidence of first CVD event. Results At baseline, the cholesterol content per LDL particle was negatively associated with triglycerides and positively associated with LDL-C. On follow-up (median 14.8 yrs), 265 men and 266 women experienced a CVD event. In multivariable models adjusting for non-lipid CVD risk factors, LDL-P was related more strongly to future CVD in both sexes than LDL-C or non-HDL-C. Subjects with a low level of LDL-P (<25th percentile) had a lower CVD event rate (59 events per 1000 person-years) than those with an equivalently low level of LDL-C or non-HDL-C (81 and 74 events per 1000 person-years, respectively). Conclusions In a large community-based sample, LDL-P was a more sensitive indicator of low CVD risk than either LDL-C or non-HDL-C, suggesting a potential clinical role for LDL-P as a goal of LDL management. PMID:19657464

  2. IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis

    PubMed Central

    Binder, Christoph J.; Hartvigsen, Karsten; Chang, Mi-Kyung; Miller, Marina; Broide, David; Palinski, Wulf; Curtiss, Linda K.; Corr, Maripat; Witztum, Joseph L.

    2004-01-01

    During atherogenesis, LDL is oxidized, generating various oxidation-specific neoepitopes, such as malondialdehyde-modified (MDA-modified) LDL (MDA-LDL) or the phosphorylcholine (PC) headgroup of oxidized phospholipids (OxPLs). These epitopes are recognized by both adaptive T cell–dependent (TD) and innate T cell–independent type 2 (TI-2) immune responses. We previously showed that immunization of mice with MDA-LDL induces a TD response and atheroprotection. In addition, a PC-based immunization strategy that leads to a TI-2 expansion of innate B-1 cells and secretion of T15/EO6 clonotype natural IgM antibodies, which bind the PC of OxPLs within oxidized LDL (OxLDL), also reduces atherogenesis. T15/EO6 antibodies inhibit OxLDL uptake by macrophages. We now report that immunization with MDA-LDL, which does not contain OxPL, unexpectedly led to the expansion of T15/EO6 antibodies. MDA-LDL immunization caused a preferential expansion of MDA-LDL–specific Th2 cells that prominently secreted IL-5. In turn, IL-5 provided noncognate stimulation to innate B-1 cells, leading to increased secretion of T15/EO6 IgM. Using a bone marrow transplant model, we also demonstrated that IL-5 deficiency led to decreased titers of T15/EO6 and accelerated atherosclerosis. Thus, IL-5 links adaptive and natural immunity specific to epitopes of OxLDL and protects from atherosclerosis, in part by stimulating the expansion of atheroprotective natural IgM specific for OxLDL. PMID:15286809

  3. Niacin reverses migratory macrophage foam cell arrest mediated by oxLDL in vitro.

    PubMed

    Huang, Hua; Koelle, Pirkko; Fendler, Markus; Schroettle, Angelika; Czihal, Michael; Hoffmann, Ulrich; Kuhlencordt, Peter Jan

    2014-01-01

    Niacin reduces vascular oxidative stress and down regulates inducible nitric oxide synthase, an enzyme mediating proatherosclerotic effects in part by increasing oxidative stress. Here, we evaluate whether Niacin reverses the redox sensitive migratory arrest of macrophages in response to oxidised(ox) LDL uptake. Migration of RAW264.7 cells, a murine macrophage cell line and bone marrow derived macrophages from wildtype and iNOS knockout mice was quantified using a modified Boyden chamber. Unstimulated cells or cells preincubated with oxLDL or non-oxidised (n)LDL were treated with Nicotinic acid or Nicotinamide. Nitric oxide, peroxynitrite and ROS production were assessed using electron paramagnetic resonance (ESR). Additionally, flow cytometry analysis of apoptosis, fokal adhesion kinase (FAK), phalloidin, CD36, F4/80 macrophage marker and iNOS gene expression (PCR) were assessed. Migration of Nicotinic acid, Nicotinamide treated cells or unstimulated cells did not differ (P>0.05). oxLDL treatment significantly reduced migration vs. unstimulated cells (p<0.05). In contrast, migratory arrest in response to oxLDL treatment was reversed by co-incubation with Nicotinic acid and Nicotinamide. The oxLDL-induced peroxynitrite formation in RAW264.7 cells was abolished by Niacin and glutathion (GSH) oxidation was significantly reduced. However, nitric oxide (NO)- and reactive oxygen species (ROS) production induced by oxLDL were not affected by Niacin treatment of RAW264.7 cells. In addition, Nicotinic acid and Nicotinamide reduced actin polymerization, a marker for migratory arrest. Our data shows that oxLDL induced inhibition of macrophage migration in vitro can be reversed by Niacin. Furthermore, Niacin reduces peroxynitite formation and improves antioxidant GSH.

  4. Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways

    SciTech Connect

    Chang, Chun-Yu; Shen, Chao-Yu; Kang, Chao-Kai; Sher, Yuh-Pyng; Sheu, Wayne H.-H.; Chang, Chia-Che; Lee, Tsung-Han

    2014-09-15

    Oxidized LDL (oxLDL) induces a pro-oxidative environment and promotes apoptosis, causing the progression of renal diseases in humans. Taurine is a semi-essential amino acid in mammals and has been shown to be a potent endogenous antioxidant. The kidney plays a pivotal role in maintaining the balance of taurine. However, the mechanisms underlying the protective effects of taurine against oxLDL-induced injury in renal epithelial cells have not been clarified. In the present study, we investigated the anti-apoptotic effects of taurine on human proximal tubular epithelial (HK-2) cells exposed to oxLDL and explored the related mechanisms. We observed that oxLDL increased the contents of ROS and of malondialdehyde (MDA), which is a lipid peroxidation by-product that acts as an indicator of the cellular oxidation status. In addition, oxLDL induced cell death and apoptosis in HK-2 cells. Pretreatment with taurine at 100 μM significantly attenuated the oxLDL-induced cytotoxicity. We determined that oxLDL triggered the phosphorylation of ERK and, in turn, the activation of p53 and other apoptosis-related events, including calcium accumulation, destabilization of the mitochondrial permeability and disruption of the balance between pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins. The malfunctions induced by oxLDL were effectively blocked by taurine. Thus, our results suggested that taurine exhibits potential therapeutic activity by preventing oxLDL-induced nephrotoxicity. The inhibition of oxLDL-induced epithelial apoptosis by taurine was at least partially due to its anti-oxidant activity and its ability to modulate the ERK and p53 apoptotic pathways. - Highlights: • Oxidized LDL induced cytotoxicity and apoptosis in HK-2 cells. • Pretreatment with taurine attenuated oxLDL-induced nephrotoxicity. • Taurine protected against renal damages through inhibition of ROS generation. • Taurine prevented apoptosis through modulation of the p53 phosphorylation.

  5. Protective effects of aspirin against oxidized LDL-induced inflammatory protein expression in human endothelial cells.

    PubMed

    Zhao, Jinjing; Qi, Ruomei; Li, Rui; Wu, Wei; Gao, Xin; Bao, Li; Lu, Shuzheng

    2008-01-01

    Atherosclerosis is a complex vascular inflammatory disease. Oxidized low-density lipoprotein (ox-LDL) is directly associated with chronic vascular inflammation. In this study, we hypothesized that nonselective cyclooxygenase inhibitor aspirin might affect the ox-LDL-induced inflammatory responses on human endothelial cells. To test this assumption, cyclooxygenase-2 (COX-2) and intercellular adhesion molecule-1 (ICAM-1) expression, IkappaB and p38 mitogen-activated protein kinase (MAPK) phosphorylation were determined in endothelial cells exposed to ox-LDL in the presence of aspirin. The results showed that aspirin significantly suppressed COX-2 and ICAM-1 expression induced by ox-LDL and also inhibited IkappaB phosphorylation in human umbilical vein endothelial cells (HUVECs). Moreover, aspirin reduced the level of p38 MAPK phosphorylation. Our findings suggest that aspirin can decrease inflammatory responses induced by ox-LDL, and the mechanism might be associated with NF-kappaB activation pathway and inhibition of p38 MAPK phosphorylation.

  6. Discordance of Non-HDL and Directly Measured LDL Cholesterol: Which Lipid Measure is Preferred When Calculated LDL Is Inaccurate?

    PubMed

    Baruch, Lawrence; Chiong, Valerie J; Agarwal, Sanjay; Gupta, Bhanu

    2013-01-01

    Objective. To determine if non-HDL cholesterol (N-HDL) and directly measured LDL cholesterol (D-LDL) are clinically equivalent measurements. Patients and Methods. Eighty-one subjects recruited for 2 cholesterol treatment studies had at least 1 complete fasting lipid panel and D-LDL performed simultaneously; 64 had a second assessment after 4 to 6 weeks, resulting in 145 triads of C-LDL, D-LDL, and N-HDL. To directly compare N-HDL to D-LDL and C-LDL, we normalized the N-HDL by subtracting 30 from the N-HDL (N-HDLA). Results. There was significant correlation between N-HDLA, D-LDL, and C-LDL. Correlation was significantly greater between N-HDLA and C-LDL than between N-HDLA and D-LDL. A greater than 20 mg/dL difference between measures was observed more commonly between N-HDLA and D-LDL, 29%, than between C-LDL and N-HDLA, 11% (P < 0.001), and C-LDL and D-LDL, 17% (P = 0.028). Clinical discordance was most common, and concordance was least common between N-HDL and D-LDL. Conclusions. Our findings suggest that N-HDL cholesterol and D-LDL cholesterol are not clinically equivalent and frequently discordant. As N-HDL may be superior to even C-LDL for predicting events in statin-treated patients, utilizing N-HDL to guide therapy would appear to be preferable to D-LDL when C-LDL is inaccurate.

  7. Discordance of Non-HDL and Directly Measured LDL Cholesterol: Which Lipid Measure is Preferred When Calculated LDL Is Inaccurate?

    PubMed Central

    Chiong, Valerie J.

    2013-01-01

    Objective. To determine if non-HDL cholesterol (N-HDL) and directly measured LDL cholesterol (D-LDL) are clinically equivalent measurements. Patients and Methods. Eighty-one subjects recruited for 2 cholesterol treatment studies had at least 1 complete fasting lipid panel and D-LDL performed simultaneously; 64 had a second assessment after 4 to 6 weeks, resulting in 145 triads of C-LDL, D-LDL, and N-HDL. To directly compare N-HDL to D-LDL and C-LDL, we normalized the N-HDL by subtracting 30 from the N-HDL (N-HDLA). Results. There was significant correlation between N-HDLA, D-LDL, and C-LDL. Correlation was significantly greater between N-HDLA and C-LDL than between N-HDLA and D-LDL. A greater than 20 mg/dL difference between measures was observed more commonly between N-HDLA and D-LDL, 29%, than between C-LDL and N-HDLA, 11% (P < 0.001), and C-LDL and D-LDL, 17% (P = 0.028). Clinical discordance was most common, and concordance was least common between N-HDL and D-LDL. Conclusions. Our findings suggest that N-HDL cholesterol and D-LDL cholesterol are not clinically equivalent and frequently discordant. As N-HDL may be superior to even C-LDL for predicting events in statin-treated patients, utilizing N-HDL to guide therapy would appear to be preferable to D-LDL when C-LDL is inaccurate. PMID:23710352

  8. STAT5 activation induced by diabetic LDL depends on LDL glycation and occurs via src kinase activity.

    PubMed

    Brizzi, Maria Felice; Dentelli, Patrizia; Gambino, Roberto; Cabodi, Sara; Cassader, Maurizio; Castelli, Ada; Defilippi, Paola; Pegoraro, Luigi; Pagano, Gianfranco

    2002-11-01

    Advanced glycation end products (AGEs) have been implicated in the accelerated vascular injury occurring in diabetes. We recently reported that LDL prepared from type 2 diabetic patients (dm-LDL), but not normal LDL (n-LDL) triggered signal transducers and activators of transcription STAT5 activation and p21(waf) expression in endothelial cells (ECs). The aims of the present study were to investigate the role of LDL glycation in dm-LDL- mediated signals and to analyze the molecular mechanisms leading to STAT5 activation. We found that glycated LDL (gly-LDL) triggered STAT5 activation, the formation of a prolactin inducible element (PIE)-binding complex containing STAT5, and increased p21(waf) expression through the activation of the receptor for AGE (RAGE). We also demonstrated that dm-LDL and gly-LDL, but not n-LDL treatment induced the formation of a stable complex containing the activated STAT5 and RAGE. Moreover, gly-LDL triggered src but not JAK2 kinase activity. Pretreatment with the src kinase inhibitor PP1 abrogated both STAT5 activation and the expression of p21(waf) induced by gly-LDL. Consistently, gly-LDL failed to activate STAT5 in src(-/-) fibroblasts. Collectively, our results provide evidence for the role of glycation in dm-LDL-mediated effects and for a specific role of src kinase in STAT5-dependent p21(waf) expression.

  9. ApoD mediates binding of HDL to LDL and to growing T24 carcinoma.

    PubMed

    Braesch-Andersen, Sten; Beckman, Lena; Paulie, Staffan; Kumagai-Braesch, Makiko

    2014-01-01

    Apolipoprotein (Apo) D is an important protein produced in many parts of the body. It is necessary for the development and repair of the brain and protection from oxidative stress. The purpose of this study was to investigate the extent to which apoD interacts with lipoproteins in human plasma. By using detergent-free ELISA, we show that immobilized monoclonal antibodies against apoD very efficiently bind to low density lipoprotein (LDL) from plasma; this binding is as equally efficient as binding to an anti-apoB monoclonal antibody. Adding detergent to the plasma inhibited the binding, suggesting that the binding is dependent on the presence of intact lipoprotein particles. Reversing the system by using immobilized anti-apoB revealed that the affinity of apoD for LDL is rather low, suggesting that multiple bindings are needed for a durable connection. Biosensor experiments using purified lipoproteins also showed that purified apoD and high density lipoprotein 3 (HDL3), a lipoprotein fraction rich in apoD, were both able to bind LDL very efficiently, indicating that the HDL3-LDL interaction may be a physiological consequence of the affinity of apoD for LDL. Furthermore, we found that apoD increases the binding of HDL to actively growing T24 bladder carcinoma cells but not to quiescent, contact-inhibited, confluent T24 cells. This result is especially intriguing given that the T24 supernatant only contained detectable levels of apoD after growth inhibition, raising the possibility that alternating the expression of apoD and a putative apoD-receptor could give direction to the flow of lipids. In the current paper, we conclude that apoD mediates binding of HDL to LDL and to growing T24 carcinomas, thereby highlighting the importance of apoD in lipid metabolism.

  10. Reducing elevated plasma LDL cholesterol: the central role of the LDL receptor.

    PubMed

    Vincent, J

    2014-07-01

    Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease (CVD), and reduction of elevated LDL-C reduces mortality in patients at risk. This benefit has evolved from the use of statins and knowledge of the LDL receptor (LDLR). The most potent drugs used for dyslipidemias act by mechanisms that involve this receptor. Advances in molecular genetics and understanding of the regulation of this receptor have revealed several pharmacological targets that are being explored to develop more targeted therapies for dyslipidemias.

  11. Arbitrary amplitude ion-acoustic solitary waves in electronegative plasmas with electrons featuring Tsallis distribution

    NASA Astrophysics Data System (ADS)

    Ghebache, Siham; Tribeche, Mouloud

    2017-10-01

    The problem of arbitrary amplitude ion-acoustic solitary waves (IASWs), which accompany electronegative plasmas having positive ions, negative ions, and nonextensive electrons is addressed. The energy integral equation with a new Sagdeev potential is analyzed to examine the existence regions of the IASWs. Different types of electronegative plasmas inspired from the experimental studies of Ichiki et al. (2001) are discussed. Our results show that in such plasmas IASWs, the amplitude and nature of which depend sensitively on the mass and density ratio of the positive and negative ions as well as the q-nonextensive parameter, can exist. Interestingly, one finds that our plasma model supports the coexistence of smooth rarefactive and spiky compressive IASWs. Our results complement and provide new insights on previously published findings on this problem.

  12. A valence bond study of three-center four-electron pi bonding: electronegativity vs electroneutrality.

    PubMed

    DeBlase, Andrew; Licata, Megan; Galbraith, John Morrison

    2008-12-18

    Three-center four-electron (3c4e) pi bonding systems analogous to that of the ozone molecule have been studied using modern valence bond theory. Molecules studied herein consist of combinations of first row atoms C, N, and O with the addition of H atoms where appropriate in order to preserve the 3c4e pi system. Breathing orbital valence bond (BOVB) calculations were preformed at the B3LYP/6-31G**-optimized geometries in order to determine structural weights, pi charge distributions, resonance energies, and pi bond energies. It is found that the most weighted VB structure depends on atomic electronegativity and charge distribution, with electronegativity as the dominant factor. By nature, these systems are delocalized, and therefore, resonance energy is the main contributor to pi bond energies. Molecules with a single dominant VB structure have low resonance energies and therefore low pi bond energies.

  13. Nonlinear ion-acoustic double-layers in electronegative plasmas with electrons featuring Tsallis distribution

    NASA Astrophysics Data System (ADS)

    Ghebache, Siham; Tribeche, Mouloud

    2016-04-01

    Weakly nonlinear ion-acoustic (IA) double-layers (DLs), which accompany electronegative plasmas composed of positive ions, negative ions, and nonextensive electrons are investigated. A generalized Korteweg-de Vries equation with a cubic nonlinearity is derived using a reductive perturbation method. Different types of electronegative plasmas inspired from the experimental studies of Ichiki et al. (2001) are discussed. It is shown that the IA wave phase velocity, in different mixtures of negative and positive ions, decreases as the nonextensive parameter q increases, before levelling-off at a constant value for larger q. Moreover, a relative increase of Q involves an enhancement of the IA phase velocity. Existence domains of either solitary waves or double-layers are then presented and their parametric dependence is determined. Owing to the electron nonextensivity, our present plasma model can admit compressive as well as rarefactive IA-DLs.

  14. Relating Bond Angles of Dihalo- and Tetrahydro--Methanes, -Silanes, and -Germanes to Electronegativities

    ERIC Educational Resources Information Center

    Kirschenbaum, Louis J.; Ruekberg, Ben

    2012-01-01

    Our previous work correlated bond angles of group V and group VI hydrides (AH[subscript 3]E and AH[subscript 2]E[subscript 2], respectively, where E represents a lone electron pair) to the electronegativities of the atoms using the fraction of s character to relate the two. Here we have extended the correlation to the AH[subscript 2]X[subscript 2]…

  15. The noble gases: how their electronegativity and hardness determines their chemistry.

    PubMed

    Furtado, Jonathan; De Proft, Frank; Geerlings, Paul

    2015-02-26

    The establishment of an internally consistent scale of noble gas electronegativities is a long-standing problem. In the present study, the problem is attacked via the Mulliken definition, which in recent years gained widespread use to its natural appearance in the context of conceptual density functional theory. Basic ingredients of this scale are the electron affinity and the ionization potential. Whereas the latter can be computed routinely, the instability of the anion makes the judicious choice of computational technique for evaluating electron affinities much more tricky. We opted for Puiatti's approach, extrapolating the energy of high ε solvent stabilized anions to the ε = 1 (gas phase) case. The results give negative electron affinity values, monotonically increasing (except for helium which is an outlier in most of the story) to almost zero at eka-radon in agreement with high level calculations. The stability of the B3LYP results is successfully tested both via improving the level of theory (CCSD(T)) and expanding the basis set. Combined with the ionization energies (in good agreement with experiment), an electronegativity scale is obtained displaying (1) a monotonic decrease of χ when going down the periodic table, (2) top values not for the noble gases but for the halogens, as opposed to most (extrapolation) procedures of existing scales, invariably placing the noble gases on top, and (3) noble gases having electronegativities close to the chalcogens. In the accompanying hardness scale (hardly, if ever, discussed in the literature) the noble gases turn out to be by far the farthest the hardest elements, again with a continuous decrease with increasing Z. Combining χ value of the halogens and the noble gases the Ng(δ+)F(δ-) bond polarity emerging from ab initio calculations naturally emerges. In conclusion, the chemistry of the noble gases is for a large part determined by their extreme hardness, equivalent to a high resistance to change in its

  16. Dielectric Methods of Studying the Chemical Bond and the Concept of Electronegativity

    NASA Astrophysics Data System (ADS)

    Batsanov, Stepan S.

    1982-07-01

    The history and contemporary theories of the polarisation of molecules and crystals are considered and a systematic survey is given of dipole moments and bond ionicities in molecular chemical compounds and also of the effective charges of atoms in crystals. An interpretation of these results is given from the standpoint of the electronegativity concept. Views concerning the effective valencies and coordination numbers of atoms in crystals are considered. Bibliography of 207 references.

  17. Relating Bond Angles of Dihalo- and Tetrahydro--Methanes, -Silanes, and -Germanes to Electronegativities

    ERIC Educational Resources Information Center

    Kirschenbaum, Louis J.; Ruekberg, Ben

    2012-01-01

    Our previous work correlated bond angles of group V and group VI hydrides (AH[subscript 3]E and AH[subscript 2]E[subscript 2], respectively, where E represents a lone electron pair) to the electronegativities of the atoms using the fraction of s character to relate the two. Here we have extended the correlation to the AH[subscript 2]X[subscript 2]…

  18. Effect of temperature on the uniform field breakdown strength of electronegative gases

    SciTech Connect

    Christophorou, L.G.; Mathis, R.A.; Hunter, S.R.; Carter, J.G.

    1987-03-01

    In general, the electron attachment rate constant, k/sub a/ (,UPSILON), as a function of the mean electron energy and temperature UPSILON for electronegative gases which attach electrons nondissociatively decreases greatly with UPSILON from room temperature to UPSILON less than or equal to 600K, while that for electronegative gases which attach electrons dissociatively increases with increasing UPSILON. Based on recent studies in our laboratory on k/sub a/ (,UPSILON), we investigated the variation with UPSILON (approx.295-575K) of the uniform field breakdown strength, (E/N)/sub lim/, for three classes of electronegative gases: (a) gases such as c-C/sub 4/F/sub 8/ (and c-C/sub 4/F/sub 6/, 1-C/sub 3/F/sub 6/) which attach strongly low-energy (less than or equal to 1 eV) electrons nondissociatively and for which k/sub a/ (,UPSILON), decreases precipitously with UPSILON above ambient; (b) gases such as C/sub 2/F/sub 6/ and CF/sub 3/Cl which attach electrons exclusively dissociatively and whose k/sub a/ (,UPSILON) increases with UPSILON; and (c) gases such as C/sub 3/F/sub 8/ and n-C/sub 4/F/sub 10/ which attach electrons both nondissociatively and dissociatively over a common low-energy range and whose k/sub a/ (,UPSILON) first decreases and then increases with UPSILON above ambient. The (E/N)/sub lim/(UPSILON) has been found to decrease significantly with UPSILON for (a), to decrease slowly with UPSILON for (c), and to increase slightly with UPSILON for (b). These changes in (E/N)/sub lim/ follow those in k/sub a/ (,UPSILON). A similar behavior is expected for other electronegative gaseous dielectrics in the respective three groups.

  19. Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody

    PubMed Central

    Camaré, Caroline; Trayssac, Magali; Garmy-Susini, Barbara; Mucher, Elodie; Sabbadini, Roger; Salvayre, Robert; Negre-Salvayre, Anne

    2015-01-01

    BACKGROUND AND PURPOSE Neovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect. EXPERIMENTAL APPROACH Angiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice. KEY RESULTS Human oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody. CONCLUSION AND IMPLICATIONS These data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL. PMID:25176316

  20. Resveratrol Enhances Autophagic Flux and Promotes Ox-LDL Degradation in HUVECs via Upregulation of SIRT1

    PubMed Central

    Zhang, Yanlin; Cao, Xueqin; Zhu, Wawa; Liu, Zhihua; Liu, Huihui; Zhou, Yande; Cao, Yongjun; Liu, Chunfeng; Xie, Ying

    2016-01-01

    Oxidized low-density lipoprotein- (Ox-LDL-) induced autophagy dysfunction in human vascular endothelial cells contributes to the development of atherosclerosis (AS). Resveratrol (RSV) protects against Ox-LDL-induced endothelium injury. The objective of this study was to determine the mechanisms underlying Ox-LDL-induced autophagy dysfunction and RSV-mediated protection in human umbilical vein endothelial cells (HUVECs). The results showed that Ox-LDL suppressed the expression of sirtuin 1 (SIRT1) and increased LC3-II and sequestosome 1 (p62) protein levels without altering p62 mRNA levels in HUVECs. Pretreatment with bafilomycin A1 (BafA1) to inhibit lysosomal degradation abrogated the Ox-LDL-induced increase in LC3-II protein level. Ox-LDL increased colocalization of GFP and RFP puncta in mRFP-GFP-tandem fluorescent LC3- (tf-LC3-) transfected cells. Moreover, Ox-LDL decreased the expression of mature cathepsin D and attenuated cathepsin D activity. Pretreatment with RSV increased the expression of SIRT1 and LC3-II and increased p62 protein degradation. RSV induced RFP-LC3 aggregation more than GFP-LC3 aggregation. RSV restored lysosomal function and promoted Ox-LDL degradation in HUVECs. All the protective effects of RSV were blocked after SIRT1 was knocked down. These findings demonstrated that RSV upregulated the expression of SIRT1, restored lysosomal function, enhanced Ox-LDL-induced impaired autophagic flux, and promoted Ox-LDL degradation through the autophagy-lysosome degradation pathway in HUVECs. PMID:27069532

  1. Numerical simulations of electrical asymmetry effect on electronegative plasmas in capacitively coupled rf discharge

    SciTech Connect

    Zhang Quanzhi; Jiang Wei; Wang Younian; Hou Lujing

    2011-01-01

    Recently a so-called electrical asymmetry effect (EAE), which could achieve high-degree separate control of ion flux and energy in dual-frequency capacitively coupled radio-frequency (CCRF) discharges, was discovered theoretically by Heil et al. [J. Phys. D: Appl. Phys. 41, 165202 (2008)] and was confirmed by experiments and theory/numerical simulations later on for electropositive argon discharges. In this work simulations based on particle-in-cell/Monte Carlo collision are performed to study the EAE on electronegative oxygen plasmas in geometrically symmetric CCRF discharges. Dual frequency discharges operating at 13.56 and 27.12 MHz are simulated for different pressures and the results are compared with those of electropositive argon discharges at the same conditions. It is found that in general the EAE on oxygen discharges has similar behavior as on argon discharge: The self-bias voltage {eta} increases monotonically and almost linearly with the increase in the phase angle {theta} between the two driving voltages in the range 0<{theta}<90 deg. , and the maximum ion energy varies by a factor of 3 by adjusting {theta}. However, the ion flux varies with {theta} by {+-}12% for low pressure and by {+-}15% for higher pressure, due primarily to an enhanced plasma series resonance, which then leads to dramatic changes in plasma density, power absorption and consequently the electronegativity. This may place a limitation for achieving separate control of ion energy and flux for electronegative plasma via the EAE.

  2. Space charge formation and Bohm's criterion in the edge of thermal electronegative plasma

    NASA Astrophysics Data System (ADS)

    Yasserian, Kiomars; Aslaninejad, Morteza

    2016-09-01

    The collisional electronegative plasma space charge is investigated in the presence of the thermal positive ions. The Boltzmann distribution is assumed for electrons and negative ions and fluid equations are used to treat the accelerated positive ion through the sheath region. The influence of the positive ion temperature on the profile of the space charge is obtained for different negative ion concentration and negative ion temperature for collisionless and collisional cases. It is shown that the position of the space charge peak is independent of positive ion temperature while its amplitude depends on the positive ion temperature. The presence of the negative ion leads to damping of the space charge amplitude. In addition the thermal effect of the positive ion on the kinetic energy of the ion extracted from an ion source is studied in difference of collisionality and electronegativity. It is shown that, in the presence of thermal positive ion, the influence of the negative ion temperature on the sheath characteristics disappears. It is observed that in the presence of the hot positive ion, the twofold feature of the space charge starts at higher values of negative ion temperature which is more pronounced in collisional case. Finally, the influences of the positive and negative ion temperature, as well as the electronegativity and collisionality on the net electric current are studied.

  3. oxLDL and eLDL Induced Membrane Microdomains in Human Macrophages

    PubMed Central

    Wallner, Stefan; Grandl, Margot; Liebisch, Gerhard; Peer, Markus; Orsó, Evelyn; Sigrüner, Alexander; Sobota, Andrzej; Schmitz, Gerd

    2016-01-01

    Background Extravasation of macrophages and formation of lipid-laden foam cells are key events in the development and progression of atherosclerosis. The degradation of atherogenic lipoproteins subsequently leads to alterations in cellular lipid metabolism that influence inflammatory signaling. Especially sphingolipids and ceramides are known to be involved in these processes. We therefore analyzed monocyte derived macrophages during differentiation and after loading with enzymatically (eLDL) and oxidatively (oxLDL) modified low-density lipoproteins (LDL). Methods Primary human monocytes were isolated from healthy, normolipidemic blood donors using leukapheresis and counterflow elutriation. On the fourth day of MCSF-induced differentiation eLDL (40 μg/ml) or oxLDL (80 μg/ml) were added for 48h. Lipid species were analyzed by quantitative tandem mass spectrometry. Taqman qPCR was performed to investigate transcriptional changes in enzymes involved in sphingolipid metabolism. Furthermore, membrane lipids were studied using flow cytometry and confocal microscopy. Results MCSF dependent phagocytic differentiation of blood monocytes had only minor effects on the sphingolipid composition. Levels of total sphingomyelin and total ceramide remained unchanged, while lactosylceramides, cholesterylesters and free cholesterol decreased. At the species level most ceramide species showed a reduction upon phagocytic differentiation. Loading with eLDL preferentially increased cellular cholesterol while loading with oxLDL increased cellular ceramide content. Activation of the salvage pathway with a higher mRNA expression of acid and neutral sphingomyelinase, neutral sphingomyelinase activation associated factor and glucosylceramidase as well as increased surface expression of SMPD1 were identified as potentially underlying mechanisms. Moreover, flow-cytometric analysis revealed a higher cell-surface-expression of ceramide, lactosylceramide (CDw17), globotriaosylceramide (CD77

  4. Low density lipoprotein (LDL)-antioxidant flavonoids from roots of Sophora flavescens.

    PubMed

    Jeong, Tae-Sook; Ryu, Young Bae; Kim, Hoi Young; Curtis-Long, Marcus John; An, Sojin; An, So Jin; Lee, Jin Hwan; Lee, Woo Song; Park, Ki Hun

    2008-11-01

    Oxidation of low density lipoprotein (LDL) is strongly implicated as a key process in the onset of atherosclerosis. In this study, nine alkylated (C10-C5) flavonoids from Sophora flavescens were examined for their inhibitory effects on copper-induced LDL oxidation. Of the flavonoids tested, sophoraflavanone G (1), kurarinone (2), kurarinol (3), norkurarinol (4), and kuraridin (9) inhibited the generation of thiobarbituric acid reactive substances (TBARS) with IC50s of 7.9, 14.5, 22.0, 26.9, and 17.5 microM, respectively. The most potent inhibitor, compound 1, also demonstrated significant activities in complementary in vitro investigations, such as lag time (130 min at 5 microM), relative electrophoretic mobility (REM) of ox-LDL (80% inhibition at 20 microM), and fragmentation of apoB-100 (inhibition of 71% at 20 microM). Analysis of the structures of these compounds reveals that a resorcinol moiety in the B-ring is strongly correlated with protection of LDL-oxidation.

  5. FOS Expression in Blood as a LDL-Independent Marker of Statin Treatment

    PubMed Central

    Kang, Ju-Gyeong; Sung, Ho Joong; Jawed, Sarah I.; Brenneman, Cynthia L.; Rao, Yesoda N.; Sher, Salman; Facio, Flavia M.; Biesecker, Leslie G.; Quyyumi, Arshed A.; Sachdev, Vandana; Hwang, Paul M.

    2010-01-01

    Objectives The expression of FOS, a gene critical for monocyte and macrophage function, can be inhibited by statins through the disruption of a cholesterol independent signaling pathway. In this pilot study, we hypothesized that blood FOS mRNA levels will be sensitive to statin treatment independent of LDL cholesterol levels. Methods Three cohorts at increased risk of or with cardiovascular disease (CVD) were studied. Blood FOS mRNA levels were measured before and after statin treatment or in patients under stable treatment. Results Statin treatment for three months significantly reduced blood FOS mRNA and LDL cholesterol levels. However, in subjects with similar LDL levels achieved by different doses of long term statin treatment, there was an inverse relationship between statin dose and FOS expression. Conclusions FOS mRNA levels appear to be a sensitive marker of statin treatment that is dissociated from cholesterol levels. PMID:20619839

  6. The role of mitosis in LDL transport through cultured endothelial cell monolayers.

    PubMed

    Cancel, Limary M; Tarbell, John M

    2011-03-01

    We (7) have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for >90% of the transport. We (8) have also recently shown that the permeability of bovine aortic endothelial cell monolayers is highly correlated with their rate of apoptosis and that inhibiting apoptosis lowers the permeability of the monolayers to LDL. To explore the role of mitosis in the leaky junction pathway, the microtubule-stabilizing agent paclitaxel was used to alter the rate of mitosis, and LDL flux and water flux (J(v)) were measured. Control monolayers had an average mitosis rate of 0.029%. Treatment with paclitaxel (2.5 μM) for 1.5, 3, 4.5, or 6 h yielded increasing rates of mitosis ranging from 0.099% to 1.03%. The convective permeability of LDL (P(e)) increased up to fivefold, whereas J(v) increased up to threefold, over this range of mitosis rates. We found strong correlations between the mitosis rate and both P(e) and J(v). However, compared with our previous apoptosis study (8), we found that mitosis was only half as effective as apoptosis in increasing P(e). The results led us to conclude that while mitosis-related leaky junctions might play a role in the initial infiltration of LDL into the artery wall, the progression of atherosclerosis might be more closely correlated with apoptosis-related leaky junctions.

  7. The role of mitosis in LDL transport through cultured endothelial cell monolayers

    PubMed Central

    Cancel, Limary M.

    2011-01-01

    We (7) have previously shown that leaky junctions associated with dying or dividing cells are the dominant pathway for LDL transport under convective conditions, accounting for >90% of the transport. We (8) have also recently shown that the permeability of bovine aortic endothelial cell monolayers is highly correlated with their rate of apoptosis and that inhibiting apoptosis lowers the permeability of the monolayers to LDL. To explore the role of mitosis in the leaky junction pathway, the microtubule-stabilizing agent paclitaxel was used to alter the rate of mitosis, and LDL flux and water flux (Jv) were measured. Control monolayers had an average mitosis rate of 0.029%. Treatment with paclitaxel (2.5 μM) for 1.5, 3, 4.5, or 6 h yielded increasing rates of mitosis ranging from 0.099% to 1.03%. The convective permeability of LDL (Pe) increased up to fivefold, whereas Jv increased up to threefold, over this range of mitosis rates. We found strong correlations between the mitosis rate and both Pe and Jv. However, compared with our previous apoptosis study (8), we found that mitosis was only half as effective as apoptosis in increasing Pe. The results led us to conclude that while mitotsis-related leaky junctions might play a role in the initial infiltration of LDL into the artery wall, the progression of atherosclerosis might be more closely correlated with apoptosis-related leaky junctions. PMID:21169397

  8. Human plasma paraoxonase 1 (PON1) arylesterase activity during aging: correlation with susceptibility of LDL oxidation.

    PubMed

    Mehdi, Mohammad Murtaza; Rizvi, Syed Ibrahim

    2012-08-01

    The role of free radicals has long been proposed as a cause for the aging process. Oxidative stress is considered a major factor for altering many physiological processes and enzymatic activities during aging and is also known to play a major role in the development of several age-dependent diseases. Paraoxonase 1 (PON1) is an anti-atherosclerotic enzyme that mainly prevents accumulation of lipoperoxides and inhibits the lipid oxidation in low-density lipoproteins (LDL). This study was undertaken to investigate the antioxidant behavior of PON1 by measuring its arylesterase activity. The susceptibility of LDL for oxidation and the radical scavenging activity of plasma were also measured during aging in humans. Arylesterase activity of PON1 was measured in plasma of human subjects between 20 and 81 years of age of both genders. The susceptibility of LDL for oxidation and radical scavenging activity were measured in plasma. Decrease in plasma arylesterase activity of PON1, increase in susceptibility of LDL for oxidation and decrease in plasma radical scavenging activity were observed as a function of human age. The study provides evidence of a relationship between PON1 activity, LDL oxidation and free radical scavenging activity of plasma. The present results emphasize the dependency of PON1 activity to prevailing oxidative stress during human aging. Our findings assume significance in view of the possible categorization of PON1 as a longevity gene. Copyright © 2012 IMSS. Published by Elsevier Inc. All rights reserved.

  9. Biochemical and ultrastructural analysis of. beta. -VLDL and AC-LDL metabolism by pigeon monocyte-derived macrophages in culture

    SciTech Connect

    Henson, D.A.

    1987-01-01

    It is proposed that monocyte-derived foam cells in atherosclerotic lesions of White Carneau pigeons become lipid-filled through the uptake of lipoproteins including ..beta..-migrating very low density lipoproteins (..beta..-VLDL) and acetylated low density lipoproteins (Ac-LDL). Using iodinated forms of the above lipoproteins, specific and saturable receptors for both ..beta..-VLDL and Ac-LDL were detected on the surface of White Carneau pigeon monocyte-derived macrophages in culture. Competition studies demonstrated the high degree of binding specificity for /sup 125/I-Ac-LDL. Likewise, binding of /sup 125/I-..beta..-VLDL to its receptor was significantly inhibited by excess ..beta..-VLDL, however LDL from both hyper- and normocholesterolemic pigeons were also recognized by the receptor. Upon binding of ..beta..-VLDL and Ac-LDL to their respective receptors, the lipoproteins were rapidly internalized and delivered to intracellular sites of degradation. As measured by the amount of /sup 14/C-oleate incorporated into cholesteryl /sup 14/C-oleate, the cholesterole liberated from the degradation of both ..beta..-VLDL and Ac-LDL stimulated cholesteryl ester synthesis in the pigeon cells. Using lipoproteins conjugated to colloidal gold of visualization with transmission electron microscopy, a major difference in the binding and uptake properties of ..beta..-VLDL-Gold and Ac-LDL-Gold was documented.

  10. Endoplasmic Reticulum Stress Links Oxidative Stress to Impaired Pancreatic Beta-Cell Function Caused by Human Oxidized LDL

    PubMed Central

    Favre, Dimitri; Ezanno, Hélène; Bonnefond, Amélie; Bonner, Caroline; Gmyr, Valéry; Kerr-Conte, Julie; Gauthier, Benoit R.; Widmann, Christian; Waeber, Gérard; Pattou, François; Froguel, Philippe; Abderrahmani, Amar

    2016-01-01

    Elevated plasma concentration of the pro-atherogenic oxidized low density lipoprotein cholesterol (LDL) triggers adverse effects in pancreatic beta-cells and is associated with type 2 diabetes. Here, we investigated whether the endoplasmic reticulum (ER) stress is a key player coupling oxidative stress to beta-cell dysfunction and death elicited by human oxidized LDL. We found that human oxidized LDL activates ER stress as evidenced by the activation of the inositol requiring 1α, and the elevated expression of both DDIT3 (also called CHOP) and DNAJC3 (also called P58IPK) ER stress markers in isolated human islets and the mouse insulin secreting MIN6 cells. Silencing of Chop and inhibition of ER stress markers by the chemical chaperone phenyl butyric acid (PBA) prevented cell death caused by oxidized LDL. Finally, we found that oxidative stress accounts for activation of ER stress markers induced by oxidized LDL. Induction of Chop/CHOP and p58IPK/P58IPK by oxidized LDL was mimicked by hydrogen peroxide and was blocked by co-treatment with the N-acetylcystein antioxidant. As a conclusion, the harmful effects of oxidized LDL in beta-cells requires ER stress activation in a manner that involves oxidative stress. This mechanism may account for impaired beta-cell function in diabetes and can be reversed by antioxidant treatment. PMID:27636901

  11. Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression.

    PubMed

    Yurdagul, Arif; Sulzmaier, Florian J; Chen, Xiao L; Pattillo, Christopher B; Schlaepfer, David D; Orr, A Wayne

    2016-04-15

    Oxidized low-density lipoprotein (oxLDL) accumulates early in atherosclerosis and promotes endothelial nuclear factor κB (NF-κB) activation, proinflammatory gene expression and monocyte adhesion. Like for other atherogenic factors, oxLDL-induced proinflammatory responses requires integrin-dependent focal adhesion kinase (FAK, also known as PTK2) signaling; however, the mechanism by which FAK mediates oxLDL-dependent NF-κB signaling has yet to be revealed. We now show that oxLDL induces NF-κB activation and VCAM-1 expression through FAK-dependent IκB kinase β (IKKβ, also known as IKBKB) activation. We further identify FAK-dependent activation of p90 ribosomal S6 kinase family proteins (RSK) as a crucial mediator of oxLDL-dependent IKKβ and NF-κB signaling, as inhibiting RSK blocks oxLDL-induced IKKβ and NF-κB activation, VCAM-1 expression and monocyte adhesion. Finally, transgenic mice containing a kinase-dead mutation in FAK specifically in the endothelial cells show reduced RSK activity, decreased VCAM-1 expression and reduced macrophage accumulation in regions of early atherosclerosis. Taken together, our data elucidates a new mechanism whereby oxLDL-induced endothelial FAK signaling drives an ERK-RSK pathway to activate IKKβ and NF-κB signaling and proinflammatory gene expression. © 2016. Published by The Company of Biologists Ltd.

  12. Oxidized LDL: Diversity, Patterns of Recognition, and Pathophysiology

    PubMed Central

    Volkov, Suncica; Subbaiah, Papasani V.

    2010-01-01

    Abstract Oxidative modification of LDL is known to elicit an array of pro-atherogenic responses, but it is generally underappreciated that oxidized LDL (OxLDL) exists in multiple forms, characterized by different degrees of oxidation and different mixtures of bioactive components. The variable effects of OxLDL reported in the literature can be attributed in large part to the heterogeneous nature of the preparations employed. In this review, we first describe the various subclasses and molecular composition of OxLDL, including the variety of minimally modified LDL preparations. We then describe multiple receptors that recognize various species of OxLDL and discuss the mechanisms responsible for the recognition by specific receptors. Furthermore, we discuss the contentious issues such as the nature of OxLDL in vivo and the physiological oxidizing agents, whether oxidation of LDL is a prerequisite for atherogenesis, whether OxLDL is the major source of lipids in foam cells, whether in some cases it actually induces cholesterol depletion, and finally the Janus-like nature of OxLDL in having both pro- and anti-inflammatory effects. Lastly, we extend our review to discuss the role of LDL oxidation in diseases other than atherosclerosis, including diabetes mellitus, and several autoimmune diseases, such as lupus erythematosus, anti-phospholipid syndrome, and rheumatoid arthritis. Antioxid. Redox Signal. 13, 39–75. PMID:19888833

  13. The composition and metabolism of large and small LDL

    USDA-ARS?s Scientific Manuscript database

    Decreased size and increased density of LDL have been associated with increased coronary heart disease (CHD) risk. Elevated plasma concentrations of small dense LDL (sdLDL) correlate with high plasma triglycerides and low HDL cholesterol levels. This review highlights recent findings about the met...

  14. Oxidized LDL-bound CD36 recruits a Na+/K+-ATPase-Lyn complex in macrophages that promotes atherosclerosis

    PubMed Central

    Chen, Yiliang; Kennedy, David J.; Ramakrishnan, Devi Prasadh; Yang, Moua; Huang, Wenxin; Li, Zhichuan; Xie, Zijian; Chadwick, Alexandra C.; Sahoo, Daisy; Silverstein, Roy L.

    2016-01-01

    One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have previously shown that the binding of oxidized LDL (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation. Here, we identified the plasma membrane ion transporter Na/K-ATPase as a key component in the macrophage oxLDL-CD36 signaling axis. Using peritoneal macrophages isolated from Atp1a1 heterozygous or Cd36 null mice, we demonstrated that CD36 recruited a Na/K-ATPase-Lyn complex for Lyn activation in response to oxLDL. Macrophages deficient in the α1 Na/K-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibit migration of these macrophages. Furthermore, Apoe-null mice, which are a model of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1 Na+/K+-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the α1 Na+/K+-ATPase subunit.. These findings identify Na/K-ATPase as a potential target for preventing or treating anti-atherosclerotic therapy. PMID:26350901

  15. Myeloperoxidase oxidized LDL interferes with endothelial cell motility through miR-22 and heme oxygenase 1 induction: possible involvement in reendothelialization of vascular injuries.

    PubMed

    Daher, Jalil; Martin, Maud; Rousseau, Alexandre; Nuyens, Vincent; Fayyad-Kazan, Hussein; Van Antwerpen, Pierre; Courbebaisse, Guy; Martiat, Philippe; Badran, Bassam; Dequiedt, Frank; Zouaoui Boudjeltia, Karim; Vanhamme, Luc

    2014-01-01

    Cardiovascular disease linked to atherosclerosis is the leading cause of death worldwide. Atherosclerosis is mainly linked to dysfunction in vascular endothelial cells and subendothelial accumulation of oxidized forms of LDL. In the present study, we investigated the role of myeloperoxidase oxidized LDL (Mox-LDL) in endothelial cell dysfunction. We studied the effect of proinflammatory Mox-LDL treatment on endothelial cell motility, a parameter essential for normal vascular processes such as angiogenesis and blood vessel repair. This is particularly important in the context of an atheroma plaque, where vascular wall integrity is affected and interference with its repair could contribute to progression of the disease. We investigated in vitro the effect of Mox-LDL on endothelial cells angiogenic properties and we also studied the signalling pathways that could be affected by analysing Mox-LDL effect on the expression of angiogenesis-related genes. We report that Mox-LDL inhibits endothelial cell motility and tubulogenesis through an increase in miR-22 and heme oxygenase 1 expression. Our in vitro data indicate that Mox-LDL interferes with parameters associated with angiogenesis. They suggest that high LDL levels in patients would impair their endothelial cell capacity to cope with a damaged endothelium contributing negatively to the progression of the atheroma plaque.

  16. N-acetylcysteine inhibits in vivo oxidation of native low-density lipoprotein

    PubMed Central

    Cui, Yuqi; Narasimhulu, Chandrakala A.; Liu, Lingjuan; Zhang, Qingbin; Liu, Patrick Z.; Li, Xin; Xiao, Yuan; Zhang, Jia; Hao, Hong; Xie, Xiaoyun; He, Guanglong; Cui, Lianqun; Parthasarathy, Sampath; Liu, Zhenguo

    2015-01-01

    Low-density lipoprotein (LDL) is non-atherogenic, while oxidized LDL (ox-LDL) is critical to atherosclerosis. N-acetylcysteine (NAC) has anti-atherosclerotic effect with largely unknown mechanisms. The present study aimed to determine if NAC could attenuate in vivo LDL oxidation and inhibit atherosclerosis. A single dose of human native LDL was injected intravenously into male C57BL/6 mice with and without NAC treatment. Serum human ox-LDL was detected 30 min after injection, reached the peak in 3 hours, and became undetectable in 12 hours. NAC treatment significantly reduced serum ox-LDL level without detectable serum ox-LDL 6 hours after LDL injection. No difference in ox-LDL clearance was observed in NAC-treated animals. NAC treatment also significantly decreased serum ox-LDL level in patients with coronary artery diseases and hyperlipidemia without effect on LDL level. Intracellular and extracellular reactive oxidative species (ROS) production was significantly increased in the animals treated with native LDL, or ox-LDL and in hyperlipidemic LDL receptor knockout (LDLR−/−) mice that was effectively prevented with NAC treatment. NAC also significantly reduced atherosclerotic plaque formation in hyperlipidemic LDLR−/− mice. NAC attenuated in vivo oxidation of native LDL and ROS formation from ox-LDL associated with decreased atherosclerotic plaque formation in hyperlipidemia. PMID:26536834

  17. Prevention of LDL-suppression of HMG-CoA reductase (HMGR) activity by progesterone (PG): evidence for cytochrome P-450 involvement

    SciTech Connect

    Sexton, R.C.; Gupta, A.; Panini, S.R.; Rudney, H.

    1987-05-01

    Incubation of rat intestinal epithelial cells (IEC-6) with PG has been reported by us to prevent the suppression of HMGR activity by LDL. In the present study, addition of LDL and PG to IEC-6 cells resulted in a 2 fold increase in cellular free cholesterol (CH) in 24 h, while HMGR activity remained elevated. PG did not affect the internalization and degradation of (/sup 125/I) LDL nor the accumulation of free (/sup 3/H) CH in cells incubated with (/sup 3/H-cholesteryl linoleate)-LDL. Also, PG did not affect the intracellular transport of LDL-derived (/sup 3/H) CH to the plasma membrane nor the efflux of the (/sup 3/H) CH into medium containing human high density lipoprotein. Addition of LDL to cells, in which the cellular CH was radiolabeled from (/sup 3/H) acetate, resulted in an increased formation of radiolabeled oxysterols, detected by HPLC, and a corresponding decrease in HMGR activity. PG attenuated both the LDL-induced formation of oxysterols and suppression of HMGR activity. PG inhibited cytochrome P-450 dependent oxidation of benzphetamine, aminopyrine and aniline by liver microsomes from phenobarbitol treated rats. These results suggest PG may prevent LDL suppression of HMGR activity in IEC-6 cells by inhibiting cytochrome P-450 dependent formation of regulatory oxysterols.

  18. Systematic tuning of silicon Schottky barrier height by atomic interlayers with low electronegativities

    NASA Astrophysics Data System (ADS)

    Long, Wei

    The Schottky barrier height (SBH) is of great importance to the functionality of semiconductor devices, as it governs the carrier transport across the metal-semiconductor (MS) interface. The presence of the Fermi level (FL) pinning phenomena makes tuning the SBH a difficult goal to achieve. The technique of "partisan interlayer" (PI) was proposed recently to modify the SBH, where stable adsorbate-terminated semiconductor (ATS) surfaces were used to form SBs with subsequently applied metal. When elements with large electronegativities were used to form the ATS, the PI technique was effective in reducing the n-type SBH and increasing the p-type SBH, driven by the expected transfer of charge from the semiconductor to the adsorbates. In this thesis work, elements with electronegativities smaller than that of the semiconductor are used as surface termination. SBHs for Ag, Au and In on Si surfaces are found to increase for the n-type and decrease for the p-type interfaces, by as much as 0.25eV, when Ga, Mg and K are used to terminate the Si surfaces. The present results are thus in agreement with the expected charge transfers from elements with smaller electronegativities to silicon and illustrate the general validity of the PI technique. The chemical stability of these surfaces likely weakens the MS interaction and leads to the (partial) preservation of the surface dipole at the MS interface. However, large degrees of SBH inhomogeneity are observed for diodes on these surfaces, likely due to insufficient stability of these surfaces to completely withstand metal interaction. These results are discussed within the basic models of SBH formation and the implications of these results for SBH control of MS systems are also addressed.

  19. Dust-ion-acoustic shock and solitary waves in a dusty electronegative plasma

    SciTech Connect

    Mamun, A. A.; Tasnim, S.

    2010-07-15

    A dusty electronegative plasma containing Boltzmann electrons, Boltzmann negative ions, warm positive ions, and charge fluctuating (negatively charged) stationary dust has been considered. The basic features of the shock and solitary waves, which are associated with positive ion dynamics and dust charge fluctuation, have been investigated by employing the reductive perturbation method. It has been shown that the dust charge fluctuation is a source of dissipation, and is responsible for the formation of dust-ion-acoustic shock structures. The implications of the results (obtained from this investigation) in space and laboratory experiments have been discussed.

  20. Experimental Observation and Computational Analysis of Striations in Electronegative Capacitively Coupled Radio-Frequency Plasmas.

    PubMed

    Liu, Yong-Xin; Schüngel, Edmund; Korolov, Ihor; Donkó, Zoltán; Wang, You-Nian; Schulze, Julian

    2016-06-24

    Self-organized spatial structures in the light emission from the ion-ion capacitive rf plasma of a strongly electronegative gas (CF_{4}) are observed experimentally for the first time. Their formation is analyzed and understood based on particle-based kinetic simulations. These "striations" are found to be generated by the resonance between the driving radio frequency and the eigenfrequency of the ion-ion plasma (derived from an analytical model) that establishes a modulation of the electric field, the ion densities, as well as the energy gain and loss processes of electrons in the plasma. The growth of the instability is followed by the numerical simulations.

  1. Dust-acoustic shock waves in a charge varying electronegative magnetized dusty plasma with suprathermal electrons

    SciTech Connect

    Tribeche, Mouloud; Bacha, Mustapha

    2012-12-15

    The combined effects of an oblique magnetic field and electron suprathermality on weak dust-acoustic (DA) waves in a charge varying electronegative dusty plasmas with application to the Halley Comet are investigated. The correct suprathermal electron charging current is derived based on the orbit-motion limited approach. A weakly nonlinear analysis is carried out to derive a Korteweg-de Vries-Burger equation. The electron suprathermality, the obliqueness, and magnitude of the magnetic field are found to modify the dispersive properties of the DA shock structure. Our results may aid to explain and interpret the nonlinear oscillations that may occur in the Halley Comet plasma.

  2. Effects of cocoa powder and dark chocolate on LDL oxidative susceptibility and prostaglandin concentrations in humans.

    PubMed

    Wan, Y; Vinson, J A; Etherton, T D; Proch, J; Lazarus, S A; Kris-Etherton, P M

    2001-11-01

    Flavonoids are polyphenolic compounds of plant origin with antioxidant effects. Flavonoids inhibit LDL oxidation and reduce thrombotic tendency in vitro. Little is known about how cocoa powder and dark chocolate, rich sources of polyphenols, affect these cardiovascular disease risk factors. We evaluated the effects of a diet high in cocoa powder and dark chocolate (CP-DC diet) on LDL oxidative susceptibility, serum total antioxidant capacity, and urinary prostaglandin concentrations. We conducted a randomized, 2-period, crossover study in 23 healthy subjects fed 2 diets: an average American diet (AAD) controlled for fiber, caffeine, and theobromine and an AAD supplemented with 22 g cocoa powder and 16 g dark chocolate (CP-DC diet), providing approximately 466 mg procyanidins/d. LDL oxidation lag time was approximately 8% greater (P = 0.01) after the CP-DC diet than after the AAD. Serum total antioxidant capacity measured by oxygen radical absorbance capacity was approximately 4% greater (P = 0.04) after the CP-DC diet than after the AAD and was positively correlated with LDL oxidation lag time (r = 0.32, P = 0.03). HDL cholesterol was 4% greater after the CP-DC diet (P = 0.02) than after the AAD; however, LDL-HDL ratios were not significantly different. Twenty-four-hour urinary excretion of thromboxane B(2) and 6-keto-prostaglandin F(1)(alpha) and the ratio of the 2 compounds were not significantly different between the 2 diets. Cocoa powder and dark chocolate may favorably affect cardiovascular disease risk status by modestly reducing LDL oxidation susceptibility, increasing serum total antioxidant capacity and HDL-cholesterol concentrations, and not adversely affecting prostaglandins.

  3. Is the Ratio of Antibodies Against Oxidized LDL to Oxidized LDL an Indicator of Cardiovascular Risk in Psoriasis?

    PubMed Central

    Rajappa, Medha; Mohan Thappa, Devinder; Chandrashekar, Laxmisha; Munisamy, Malathi; Revathy, G.

    2016-01-01

    Objectives Psoriasis is a chronic inflammatory skin disease. Chronic inflammation results in increased oxidative stress and oxidizes lipoproteins, increasing their atherogenicity. This study sought to estimate the levels of oxidized low-density lipoprotein (ox-LDL) and antibodies against oxidized LDL (anti-ox-LDL) and compute the ratio of anti-ox-LDL/ox-LDL as a single composite parameter to assess the oxidative lipoprotein burden as an indicator of cardiovascular risk in patients with psoriasis. Methods This cross-sectional study included 45 patients with psoriasis. All patients were given a psoriasis severity index score and their ox-LDL and anti-ox-LDL estimated using ELISA. Results The results of this study show an elevation in the ratio of anti-ox-LDL to ox-LDL in patients with psoriasis, which initiate and perpetuate the pathogenesis of psoriasis and its comorbidity, atherosclerotic cardiovascular disease. Conclusions Our results suggest that an elevated ratio of anti-ox-LDL/ox-LDL can serve as a composite parameter reflecting the total oxidative lipoprotein burden and cardiovascular risk in psoriasis patients. PMID:27602197

  4. A scale of metal ion binding strengths correlating with ionic charge, Pauling electronegativity, toxicity, and other physiological effects.

    PubMed

    Kinraide, Thomas B; Yermiyahu, Uri

    2007-09-01

    Equilibrium constants for binding to plant plasma membranes have been reported for several metal ions, based upon adsorption studies and zeta-potential measurements. LogK values for the ions are these: Al(3+), 4.30; La(3+), 3.34; Cu(2+), 2.60; Ca(2+) and Mg(2+), 1.48; Na(+) and K(+), 0 M(-1). These values correlate well with logK values for ion binding to many organic and inorganic ligands. LogK values for metal ion binding to 12 ligands were normalized and averaged to produce a scale for the binding of 49 ions. The scale correlates well with the values presented above (R(2)=0.998) and with ion binding to cell walls and other biomass. The scale is closely related to the charge (Z) and Pauling electronegativity (PE) of 48 ions (all but Hg(2+)); R(2)=0.969 for the equation (Scale values)=-1.68+Z(1.22+0.444PE). Minimum rhizotoxicity of metal ions appears to be determined by binding strengths: log a(PM,M)=1.60-2.41exp[0.238(Scale values)] determines the value of ion activities at the plasma membrane surface (a(PM,M)) that will ensure inhibition of root elongation. Additional toxicity appears to be related to softness, accounting for the great toxicity of Ag(+), for example. These binding-strength values correlate with additional physiological effects and are suitable for the computation of cell-surface electrical potentials.

  5. A DNA minor groove electronegative potential genome map based on photo-chemical probing.

    PubMed

    Lindemose, Søren; Nielsen, Peter Eigil; Hansen, Morten; Møllegaard, Niels Erik

    2011-08-01

    The double-stranded DNA of the genome contains both sequence information directly relating to the protein and RNA coding as well as functional and structural information relating to protein recognition. Only recently is the importance of DNA shape in this recognition process being fully appreciated, and it also appears that minor groove electronegative potential may contribute significantly in guiding proteins to their cognate binding sites in the genome. Based on the photo-chemical probing results, we have derived an algorithm that predicts the minor groove electronegative potential in a DNA helix of any given sequence. We have validated this model on a series of protein-DNA binding sites known to involve minor groove electrostatic recognition as well as on stable nucleosome core complexes. The algorithm allows for the first time a full minor groove electrostatic description at the nucleotide resolution of any genome, and it is illustrated how such detailed studies of this sequence dependent, inherent property of the DNA may reflect on genome organization, gene expression and chromosomal condensation.

  6. Use of infrared spectroscopy for the determination of electronegativity of rare earth elements.

    PubMed

    Frost, Ray L; Erickson, Kristy L; Weier, Matt L; McKinnon, Adam R; Williams, Peter A; Leverett, Peter

    2004-07-01

    Infrared spectroscopy has been used to study a series of synthetic agardite minerals. Four OH stretching bands are observed at around 3568, 3482, 3362, and 3296 cm(-1). The first band is assigned to zeolitic, non-hydrogen-bonded water. The band at 3296 cm(-1) is assigned to strongly hydrogen-bonded water with an H bond distance of 2.72 A. The water in agardites is better described as structured water and not as zeolitic water. Two bands at around 999 and 975 cm(-1) are assigned to OH deformation modes. Two sets of AsO symmetric stretching vibrations were found and assigned to the vibrational modes of AsO(4) and HAsO(4) units. Linear relationships between positions of infrared bands associated with bonding to the OH units and the electronegativity of the rare earth elements were derived, with correlation coefficients >0.92. These linear functions were then used to calculate the electronegativity of Eu, for which a value of 1.1808 on the Pauling scale was found.

  7. An expression for the h l factor in low-pressure electronegative plasma discharges

    NASA Astrophysics Data System (ADS)

    Chabert, P.

    2016-04-01

    The positive ion flux exiting a low-pressure plasma discharge is a crucial quantity in global (volume-averaged) models. In discharges containing only electrons and positive ions (electropositive discharges), it is common to write this flux {Γ\\text{wall}}={{h}\\text{l}}{{n}\\text{i0}}{{u}\\text{B}} , where {{n}\\text{i0}} is the central positive ion density, {{u}\\text{B}} is the positive ion fluid speed at the sheath edge (the Bohm speed), and {{h}\\text{l}} is the positive ion edge-to-centre density ratio. There are well established formulae for {{h}\\text{l}} in electropositive discharges, but for discharges containing negative ions (electronegative discharges), the analysis is more complicated. The purpose of this paper is to propose a formula for the {{h}\\text{l}} factor in low-pressure electronegative discharges. We use the numerical solution of fluid equations with Boltzmann negative ions, including Poisson’s equation, as a guide to derive an analytical expression that can easily be incorporated in global models. The parameter space in which the derived expression is valid is discussed at the end of the paper.

  8. Early Transcriptomic Response to LDL and oxLDL in Human Vascular Smooth Muscle Cells

    PubMed Central

    Damián-Zamacona, Salvador; Toledo-Ibelles, Paola; Ibarra-Abundis, Mabel Z.; Uribe-Figueroa, Laura; Hernández-Lemus, Enrique; Macedo-Alcibia, Karla Paola; Delgado–Coello, Blanca; Mas-Oliva, Jaime; Reyes-Grajeda, Juan Pablo

    2016-01-01

    Background Although nowadays it is well known that the human transcriptome can importantly vary according to external or environmental condition, the reflection of this concept when studying oxidative stress and its direct relationship with gene expression profiling during the process of atherogenesis has not been thoroughly achieved. Objective The ability to analyze genome-wide gene expression through transcriptomics has shown that the genome responds dynamically to diverse stimuli. Here, we describe the transcriptome of human vascular smooth muscle cells (hVSMC) stimulated by native and oxidized low-density lipoprotein (nLDL and oxLDL respectively), with the aim of assessing the early molecular changes that induce a response in this cell type resulting in a transcriptomic transformation. This expression has been demonstrated in atherosclerotic plaques in vivo and in vitro, particularly in the light of the oxidative modification hypothesis of atherosclerosis. Approach and Results Total RNA was isolated with TRIzol reagent (Life Technologies) and quality estimated using an Agilent 2100 bioanalyzer. The transcriptome of hVSMC under different experimental conditions (1,5 and 24 hours for nLDL and oxLDL) was obtained using the GeneChip Human Gene 1.0 ST (Affymetrix) designed to measure gene expression of 28,869 well-annotated genes. A fixed fold-change cut-off corresponding to ± 2 was used to identify genes exhibiting the most significant variation and statistical significance (P< 0.05), and 8 genes validated by qPCR using Taqman probes. Conclusions 10 molecular processes were significantly affected in hVSMC: Apoptosis and cell cycle, extracellular matrix remodeling, DNA repair, cholesterol efflux, cGMP biosynthesis, endocytic mechanisms, calcium homeostasis, redox balance, membrane trafficking and finally, the immune response to inflammation. The evidence we present supporting the hypothesis for the involvement of oxidative modification of several processes and

  9. The N342S MYLIP polymorphism is associated with high total cholesterol and increased LDL receptor degradation in humans

    PubMed Central

    Weissglas-Volkov, Daphna; Calkin, Anna C.; Tusie-Luna, Teresa; Sinsheimer, Janet S.; Zelcer, Noam; Riba, Laura; Tino, Ana Maria Vargas; Ordoñez-Sánchez, Maria Luisa; Cruz-Bautista, Ivette; Aguilar-Salinas, Carlos A.; Tontonoz, Peter; Pajukanta, Päivi

    2011-01-01

    Atherosclerotic cardiovascular disease (ASCVD) affects more than 1 in 3 American adults. Hypercholesterolemia is a major treatable risk factor for ASCVD, yet many individuals fail to reach target levels of LDL-cholesterol (LDL-C) through the use of statins and lifestyle changes. The E3 ubiquitin ligase myosin regulatory light chain–interacting protein (MYLIP; also known as IDOL) is a recently identified regulator of the LDL receptor (LDLR) pathway. Genome-wide association studies (GWASs) in populations of mixed European descent have identified noncoding variants in the MYLIP region as being associated with LDL-C levels, but no underlying functional variants were pinpointed. In order to fine-map actual susceptibility variants, we studied a population demographically distinct from the discovery population to ensure a different pattern of linkage disequilibrium. Our analysis revealed that in a Mexican population, the nonsynonymous SNP rs9370867, which encodes the N342S amino acid substitution, is an underlying functional variant that was associated with high total cholesterol and accounted for one of the previous significant GWAS signals. Functional characterization showed that the Asn-encoding allele was associated with more potent LDLR degradation and decreased LDL uptake. Mutagenesis of residue 342 failed to affect intrinsic MYLIP E3 ligase activity, but it was critical for LDLR targeting. Our findings suggest that modulation of MYLIP activity can affect LDL-C levels and that pharmacologic inhibition of MYLIP activity might be a useful strategy in the treatment of dyslipidemia and ASCVD. PMID:21765216

  10. Having excess levels of PCSK9 is not sufficient to induce complex formation between PCSK9 and the LDL receptor.

    PubMed

    Wooten, Catherine J; Adcock, Audrey F; Agina-Obu, DaTonye I; Lopez, Dayami

    2014-03-01

    Proprotein convertase subtilisin/kexin-9 (PCSK9) acts mainly by forming complexes with the LDL receptor at the cell surface, which are then degraded in the lysosome. Studies were performed to determine whether excess levels of PCSK9 was sufficient to induce PCSK9/LDL receptor complex formation in human hepatocyte-like C3A cells. It was demonstrated using ELISA that instead of considering the overall levels of PCSK9 protein that is produced in response to certain treatment, what is critical is how much PCSK9 is actually capable of forming complexes. Despite the high levels, most of the PCSK9 produced as a result of incubating cells with a medium supplemented with BD™ MITO+ serum extender (MITO+ medium) appeared to be inhibited by a secreted factor. Having lower levels of PCSK9/LDL receptor complexes did not prevent an increase in the degradation rate of LDL receptors in MITO+ medium as compared to fetal bovine serum (FBS) containing medium (Regular medium), an effect that did not correlate with an increase in protein levels of the inducible degrader of LDL receptors (IDOL), as demonstrated using Western blotting analysis. Additional studies are required to determine the exact mechanism(s) for the degradation of the LDL receptor and/or to identify the secreted inhibitor of PCSK9.

  11. Plasma high density lipoprotein is increased in man when low density lipoprotein (LDL) is lowered by LDL-pheresis.

    PubMed Central

    Parker, T S; Gordon, B R; Saal, S D; Rubin, A L; Ahrens, E H

    1986-01-01

    Plasma high density lipoprotein (HDL) concentrations were increased in five hypercholesterolemic normoglyceridemic patients after removal of plasma low density lipoprotein (LDL) by LDL-pheresis. In each patient up to 80% of circulating LDL was removed by passing plasma through immunoadsorption columns containing antibody to apolipoprotein B immobilized to Sepharose. Rebound of LDL was slow after the procedure: 5-7 days in four non-familial hypercholesterolemic patients and greater than 14 days in one patient with homozygous familial hypercholesterolemia. Plasma HDL rose above the pretreatment baseline during the interval between treatments in four of the five patients. When treatments were repeated weekly, time-averaged plasma LDL was lowered by 40-70%, while plasma HDL cholesterol and apolipoprotein AI were increased up to 2-fold, depending on the degree of LDL lowering. Plasma HDL concentrations fell back to their baseline values when LDL-pheresis was stopped and rose again when treatment was restarted. Thus, LDL-pheresis may augment the therapeutic effectiveness of LDL lowering by raising plasma HDL levels and the concentration of HDL relative to LDL. PMID:3511474

  12. High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans

    PubMed Central

    Jones, Peter J. H.; MacKay, Dylan. S.; Senanayake, Vijitha K.; Pu, Shuaihua; Jenkins, David J. A.; Connelly, Philip W.; Lamarche, Benoît; Couture, Patrick; Kris-Etherton, Penny M.; West, Sheila G.; Liu, Xiaoran; Fleming, Jennifer A.; Hantgan, Roy R.; Rudel, Lawrence L.

    2015-01-01

    Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets; 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p=0.0005 and p=0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p=0.0243) and DHA-enriched high oleic canola oil (p=0.0249), although high-oleic canola oil had the lowest binding at baseline (p=0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding. PMID:25528432

  13. High-oleic canola oil consumption enriches LDL particle cholesteryl oleate content and reduces LDL proteoglycan binding in humans.

    PubMed

    Jones, Peter J H; MacKay, Dylan S; Senanayake, Vijitha K; Pu, Shuaihua; Jenkins, David J A; Connelly, Philip W; Lamarche, Benoît; Couture, Patrick; Kris-Etherton, Penny M; West, Sheila G; Liu, Xiaoran; Fleming, Jennifer A; Hantgan, Roy R; Rudel, Lawrence L

    2015-02-01

    Oleic acid consumption is considered cardio-protective according to studies conducted examining effects of the Mediterranean diet. However, animal models have shown that oleic acid consumption increases LDL particle cholesteryl oleate content which is associated with increased LDL-proteoglycan binding and atherosclerosis. The objective was to examine effects of varying oleic, linoleic and docosahexaenoic acid consumption on human LDL-proteoglycan binding in a non-random subset of the Canola Oil Multi-center Intervention Trial (COMIT) participants. COMIT employed a randomized, double-blind, five-period, cross-over trial design. Three of the treatment oil diets: 1) a blend of corn/safflower oil (25:75); 2) high oleic canola oil; and 3) DHA-enriched high oleic canola oil were selected for analysis of LDL-proteoglycan binding in 50 participants exhibiting good compliance. LDL particles were isolated from frozen plasma by gel filtration chromatography and LDL cholesteryl esters quantified by mass-spectrometry. LDL-proteoglycan binding was assessed using surface plasmon resonance. LDL particle cholesterol ester fatty acid composition was sensitive to the treatment fatty acid compositions, with the main fatty acids in the treatments increasing in the LDL cholesterol esters. The corn/safflower oil and high-oleic canola oil diets lowered LDL-proteoglycan binding relative to their baseline values (p = 0.0005 and p = 0.0012, respectively). At endpoint, high-oleic canola oil feeding resulted in lower LDL-proteoglycan binding than corn/safflower oil (p = 0.0243) and DHA-enriched high oleic canola oil (p = 0.0249), although high-oleic canola oil had the lowest binding at baseline (p = 0.0344). Our findings suggest that high-oleic canola oil consumption in humans increases cholesteryl oleate percentage in LDL, but in a manner not associated with a rise in LDL-proteoglycan binding.

  14. Effect of bulk electric field reversal on the bounce resonance heating in dual-frequency capacitively coupled electronegative plasmas

    SciTech Connect

    Liu Yongxin; Zhang Quanzhi; Liu Jia; Song Yuanhong; Wang Younian; Bogaerts, Annemie

    2012-09-10

    The electron bounce resonance heating (BRH) in dual-frequency capacitively coupled plasmas operated in oxygen and argon has been studied by different experimental methods. In comparison with the electropositive argon discharge, the BRH in an electronegative discharge occurs at larger electrode gaps. Kinetic particle simulations reveal that in the oxygen discharge, the bulk electric field becomes quite strong and is out of phase with the sheath field. Therefore, it retards the resonant electrons when traversing the bulk, resulting in a suppressed BRH. This effect becomes more pronounced at lower high-frequency power, when the discharge mode changes from electropositive to electronegative.

  15. Oxidized LDL lipids increase β-amyloid production by SH-SY5Y cells through glutathione depletion and lipid raft formation.

    PubMed

    Dias, Irundika H K; Mistry, Jayna; Fell, Shaun; Reis, Ana; Spickett, Corinne M; Polidori, Maria C; Lip, Gregory Y H; Griffiths, Helen R

    2014-10-01

    Elevated total cholesterol in midlife has been associated with increased risk of dementia in later life. We have previously shown that low-density lipoprotein (LDL) is more oxidized in the plasma of dementia patients, although total cholesterol levels are not different from those of age-matched controls. β-Amyloid (Aβ) peptide, which accumulates in Alzheimer disease (AD), arises from the initial cleavage of amyloid precursor protein by β-secretase-1 (BACE1). BACE1 activity is regulated by membrane lipids and raft formation. Given the evidence for altered lipid metabolism in AD, we have investigated a mechanism for enhanced Aβ production by SH-SY5Y neuronal-like cells exposed to oxidized LDL (oxLDL). The viability of SH-SY5Y cells exposed to 4μg oxLDL and 25µM 27-hydroxycholesterol (27OH-C) was decreased significantly. Lipids, but not proteins, extracted from oxLDL were more cytotoxic than oxLDL. In parallel, the ratio of reduced glutathione (GSH) to oxidized glutathione was decreased at sublethal concentrations of lipids extracted from native and oxLDL. GSH loss was associated with an increase in acid sphingomyelinase (ASMase) activity and lipid raft formation, which could be inhibited by the ASMase inhibitor desipramine. 27OH-C and total lipids from LDL and oxLDL independently increased Aβ production by SH-SY5Y cells, and Aβ accumulation could be inhibited by desipramine and by N-acetylcysteine. These data suggest a mechanism whereby oxLDL lipids and 27OH-C can drive Aβ production by GSH depletion, ASMase-driven membrane remodeling, and BACE1 activation in neuronal cells. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

  16. Ceramide Mediates Ox-LDL-Induced Human Vascular Smooth Muscle Cell Calcification via p38 Mitogen-Activated Protein Kinase Signaling

    PubMed Central

    Song, Yan; Wu, Weikang; Yu, Huimin; Wang, Sheng; Chen, Yanling; Ye, Meihong; Lu, Lihe

    2013-01-01

    Vascular calcification is associated with significant cardiovascular morbidity and mortality, and has been demonstrated as an actively regulated process resembling bone formation. Oxidized low density lipoprotein (Ox-LDL) has been identified as a regulatory factor involved in calcification of vascular smooth muscle cells (VSMCs). Additionally, over-expression of recombinant human neutral sphingomyelinase (N-SMase) has been shown to stimulate VSMC apoptosis, which plays an important role in the progression of vascular calcification. The aim of this study is to investigate whether ceramide regulates Ox-LDL-induced calcification of VSMCs via activation of p38 mitogen-activated protein kinase (MAPK) pathway. Ox-LDL increased the activity of N-SMase and the level of ceramide in cultured VSMCs. Calcification and the osteogenic transcription factor, Msx2 mRNA expression were reduced by N-SMase inhibitor, GW4869 in the presence of Ox-LDL. Usage of GW4869 inhibited Ox-LDL-induced apoptosis in VSMCs, an effect which was reversed by C2-ceramide. Additionally, C2-ceramide treatment accelerated VSMC calcification, with a concomitant increase in ALP activity. Furthermore, C2-ceramide treatment enhanced Ox-LDL-induced VSMC calcification. Addition of caspase inhibitor, ZVAD-fmk attenuated Ox-LDL-induced calcification. Both Ox-LDL and C2-ceramide treatment increased the phosphorylation of p38 MAPK. Inhibition of p38 MAPK by SB203580 attenuated Ox-LDL-induced calcification of VSMCs. These data suggest that Ox-LDL activates N-SMase-ceramide signaling pathway, and stimulates phosphorylation of p38 MAPK, leading to apoptosis in VSMCs, which initiates VSMC calcification. PMID:24358176

  17. Effect of Selenium-Enriched Garlic Oil against Cytotoxicity Induced by OX-LDL in Endothelial Cells.

    PubMed

    Yang, Cheng; Cui, Kai; Diao, Yutao; Du, Min; Wang, Shumei

    2014-01-01

    Objective. To detect the effect of selenium-enriched garlic oil (Se-garlic oil) against cytotoxicity induced by ox-LDL in endothelial cells. Methods. Se-garlic oil was extracted by organic solvent extraction. High performance liquid chromatography (HPLC) was used to detect the content of allicin in the Se-garlic oil. Hydride generation atomic fluorescence spectrometry (HG-AFS) was used to detect the content of Se in the Se-garlic oil. ECV-304 cells were separated into five groups (blank, ox-LDL, and low-, medium-, and high-dose Se-garlic oil). Methyl thiazolyl tetrazolium (MTT) assay was used to detect the cytoactivity of each cell group after culturing for 24, 48, and 72 hours. Flow cytometry (FCM) stained with annexin V-FITC/PI was used to detect the apoptosis of the cells from the blank, Se-garlic oil, ox-LDL, and Se-garlic oil + ox-ldl groups after 48 hours of incubation. Results. The amount of allicin in Se-garlic oil was 142.66 mg/ml, while, in Se, it was 198 mg/kg. When ox-LDL was added to low-, medium-, and high-dose Se-garlic oil, the cell viability rates of ECV-304 cells treated in the three groups were all higher, while the apoptosis rates were significantly lower than those of the ox-LDL group (P < 0.05). However, there was no significant difference between the apoptosis rates of the blank, Se-garlic oil, and Se-garlic oil + ox-LDL groups (P > 0.05). Conclusion. Se-garlic oil could inhibit the cytotoxic effect induced by ox-LDL in endothelial cells.

  18. Effect of Selenium-Enriched Garlic Oil against Cytotoxicity Induced by OX-LDL in Endothelial Cells

    PubMed Central

    Cui, Kai; Diao, Yutao; Du, Min; Wang, Shumei

    2014-01-01

    Objective. To detect the effect of selenium-enriched garlic oil (Se-garlic oil) against cytotoxicity induced by ox-LDL in endothelial cells. Methods. Se-garlic oil was extracted by organic solvent extraction. High performance liquid chromatography (HPLC) was used to detect the content of allicin in the Se-garlic oil. Hydride generation atomic fluorescence spectrometry (HG-AFS) was used to detect the content of Se in the Se-garlic oil. ECV-304 cells were separated into five groups (blank, ox-LDL, and low-, medium-, and high-dose Se-garlic oil). Methyl thiazolyl tetrazolium (MTT) assay was used to detect the cytoactivity of each cell group after culturing for 24, 48, and 72 hours. Flow cytometry (FCM) stained with annexin V-FITC/PI was used to detect the apoptosis of the cells from the blank, Se-garlic oil, ox-LDL, and Se-garlic oil + ox-ldl groups after 48 hours of incubation. Results. The amount of allicin in Se-garlic oil was 142.66 mg/ml, while, in Se, it was 198 mg/kg. When ox-LDL was added to low-, medium-, and high-dose Se-garlic oil, the cell viability rates of ECV-304 cells treated in the three groups were all higher, while the apoptosis rates were significantly lower than those of the ox-LDL group (P < 0.05). However, there was no significant difference between the apoptosis rates of the blank, Se-garlic oil, and Se-garlic oil + ox-LDL groups (P > 0.05). Conclusion. Se-garlic oil could inhibit the cytotoxic effect induced by ox-LDL in endothelial cells. PMID:24987429

  19. Expression of lectin-like oxidized LDL receptor-1 in smooth muscle cells after vascular injury

    SciTech Connect

    Eto, Hideyuki; Miyata, Masaaki . E-mail: miyatam@m3.kufm.kagoshima-u.ac.jp; Kume, Noriaki; Minami, Manabu; Itabe, Hiroyuki; Orihara, Koji; Hamasaki, Shuichi; Biro, Sadatoshi; Otsuji, Yutaka; Kita, Toru; Tei, Chuwa

    2006-03-10

    Lectin-like oxidized LDL receptor-1 (LOX-1) is an oxidized LDL receptor, and its role in restenosis after angioplasty remains unknown. We used a balloon-injury model of rabbit aorta, and reverse transcription-polymerase chain reaction revealed that LOX-1 mRNA expression was modest in the non-injured aorta, reached a peak level 2 days after injury, and remained elevated until 24 weeks after injury. Immunohistochemistry and in situ hybridization showed that LOX-1 was not detected in the media of non-injured aorta but expressed in both medial and neointimal smooth muscle cells (SMC) at 2 and 24 weeks after injury. Low concentrations of ox-LDL (10 {mu}g/mL) stimulated the cultured SMC proliferation, which was inhibited by antisense oligonucleotides of LOX-1 mRNA. Double immunofluorescense staining showed the colocalization of LOX-1 and proliferating cell nuclear antigen in human restenotic lesion. These results suggest that LOX-1 mediates ox-LDL-induced SMC proliferation and plays a role in neointimal formation after vascular injury.

  20. Activation of PKC{beta}{sub II} and PKC{theta} is essential for LDL-induced cell proliferation of human aortic smooth muscle cells via Gi-mediated Erk1/2 activation and Egr-1 upregulation

    SciTech Connect

    Heo, Kyung-Sun; Kim, Dong-Uk; Kim, Lila; Nam, Miyoung; Baek, Seung-Tae; Park, Song-Kyu; Park, Youngwoo; Myung, Chang-Seon; Hwang, Sung-Ook Hoe, Kwang-Lae

    2008-03-28

    Native LDL may be a mitogenic stimulus of VSMC proliferation in lesions where endothelial disruption occurs. Recent studies have demonstrated that the mitogenic effects of LDL are accompanied by Erk1/2 activation via an unknown G-protein-coupled receptor (GPCR). In this article, we report that LDL translocated PKC{beta}{sub II} and PKC{theta} from cytosol to plasma membrane, and inhibition of PKC{beta}{sub II} and PKC{theta} decreased LDL effects via the deactivation of Erk1/2. Moreover, pertussis toxin, but not cholera toxin or heparin, inhibited LDL-induced translocation of PKC{beta}{sub II} and PKC{theta}, suggesting that Gi protein plays a role in LDL effects. Of LPA, S1P, and LDL, whose signaling is conveyed via Gi/o proteins, only LDL induced translocation of PKC{beta}{sub II} and PKC{theta}. Inhibition of PKC{beta}{sub II} or PKC{theta}, as well as of Erk1/2 and GPCR, decreases LDL-induced upregulation of Egr-1, which is critical for cell proliferation. This is the first report, to our knowledge, that the participation of PKC{theta} in VSMC proliferation is unique.

  1. VEGF-A Regulates Cellular Localization of SR-BI as Well as Transendothelial Transport of HDL but Not LDL.

    PubMed

    Velagapudi, Srividya; Yalcinkaya, Mustafa; Piemontese, Antonio; Meier, Roger; Nørrelykke, Simon Flyvbjerg; Perisa, Damir; Rzepiela, Andrzej; Stebler, Michael; Stoma, Szymon; Zanoni, Paolo; Rohrer, Lucia; von Eckardstein, Arnold

    2017-05-01

    Low- and high-density lipoproteins (LDL and HDL) must pass the endothelial layer to exert pro- and antiatherogenic activities, respectively, within the vascular wall. However, the rate-limiting factors that mediate transendothelial transport of lipoproteins are yet little known. Therefore, we performed a high-throughput screen with kinase drug inhibitors to identify modulators of transendothelial LDL and HDL transport. Microscopy-based high-content screening was performed by incubating human aortic endothelial cells with 141 kinase-inhibiting drugs and fluorescent-labeled LDL or HDL. Inhibitors of vascular endothelial growth factor (VEGF) receptors (VEGFR) significantly decreased the uptake of HDL but not LDL. Silencing of VEGF receptor 2 significantly decreased cellular binding, association, and transendothelial transport of (125)I-HDL but not (125)I-LDL. RNA interference with VEGF receptor 1 or VEGF receptor 3 had no effect. Binding, uptake, and transport of HDL but not LDL were strongly reduced in the absence of VEGF-A from the cell culture medium and were restored by the addition of VEGF-A. The restoring effect of VEGF-A on endothelial binding, uptake, and transport of HDL was abrogated by pharmacological inhibition of phosphatidyl-inositol 3 kinase/protein kinase B or p38 mitogen-activated protein kinase, as well as silencing of scavenger receptor BI. Moreover, the presence of VEGF-A was found to be a prerequisite for the localization of scavenger receptor BI in the plasma membrane of endothelial cells. The identification of VEGF as a regulatory factor of transendothelial transport of HDL but not LDL supports the concept that the endothelium is a specific and, hence, druggable barrier for the entry of lipoproteins into the vascular wall. © 2017 American Heart Association, Inc.

  2. α-Defensins Induce a Post-translational Modification of Low Density Lipoprotein (LDL) That Promotes Atherosclerosis at Normal Levels of Plasma Cholesterol.

    PubMed

    Abu-Fanne, Rami; Maraga, Emad; Abd-Elrahman, Ihab; Hankin, Aviel; Blum, Galia; Abdeen, Suhair; Hijazi, Nuha; Cines, Douglas B; Higazi, Abd Al-Roof

    2016-02-05

    Approximately one-half of the patients who develop clinical atherosclerosis have normal or only modest elevations in plasma lipids, indicating that additional mechanisms contribute to pathogenesis. In view of increasing evidence that inflammation contributes to atherogenesis, we studied the effect of human neutrophil α-defensins on low density lipoprotein (LDL) trafficking, metabolism, vascular deposition, and atherogenesis using transgenic mice expressing human α-defensins in their polymorphonuclear leukocytes (Def(+/+)). Accelerated Def(+/+) mice developed α-defensin·LDL complexes that accelerate the clearance of LDL from the circulation accompanied by enhanced vascular deposition and retention of LDL, induction of endothelial cathepsins, increased endothelial permeability to LDL, and the development of lipid streaks in the aortic roots when fed a regular diet and at normal plasma levels of LDL. Transplantation of bone marrow from Def(+/+) to WT mice increased LDL clearance, increased vascular permeability, and increased vascular deposition of LDL, whereas transplantation of WT bone marrow to Def(+/+) mice prevented these outcomes. The same outcome was obtained by treating Def(+/+) mice with colchicine to inhibit the release of α-defensins. These studies identify a potential new link between inflammation and the development of atherosclerosis. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  3. Periodontal treatment decreases plasma oxidized LDL level and oxidative stress.

    PubMed

    Tamaki, Naofumi; Tomofuji, Takaaki; Ekuni, Daisuke; Yamanaka, Reiko; Morita, Manabu

    2011-12-01

    Periodontitis induces excessive production of reactive oxygen species in periodontal lesions. This may impair circulating pro-oxidant/anti-oxidant balance and induce the oxidation of low-density lipoprotein (LDL) in blood. The purpose of this study was to monitor circulating oxidized LDL and oxidative stress in subjects with chronic periodontitis following non-surgical periodontal treatment. Plasma levels of oxidized LDL and oxidative stress in 22 otherwise healthy non-smokers with chronic periodontitis (mean age 44.0 years) were measured at baseline and at 1 and 2 months after non-surgical periodontal treatment. At baseline, chronic periodontitis patients had higher plasma levels of oxidized LDL and oxidative stress than healthy subjects (p < 0.001). Periodontal treatment was associated with a significant reduction in plasma levels of oxidized LDL (oxLDL)(p < 0.001) and oxidative stress (p < 0.001). At 2 months after periodontal treatment, the degree of change in the oxLDL was positively correlated with that in the oxidative stress (r = 0.593, p = 0.004). These observations indicate that periodontitis patients showed higher levels of circulating oxLDL and oxidative stress than healthy subjects. In addition, improved oral hygiene and non-surgical periodontal treatment were effective in decreasing oxLDL, which was positively associated with a reduction in circulating oxidative stress.

  4. [PCSK9 Inhibitors - the magic bullet for LDL cholesterol reduction?].

    PubMed

    Richter, Kurt; Barthel, Andreas; Bornstein, Stefan R; El-Armouche, Ali; Wagner, Michael

    2016-06-01

    The proprotein convertase subtilisin / kexin type 9 (PCSK9) plays an important role in LDL cholesterol (LDL-C) metabolism. Subjects harboring loss-of-function mutations in the gene encoding for PCSK9 display markedly reduced LDL-C plasma levels. PCSK9 is secreted by the liver, binds to the LDL receptor and, following endocytosis, induces lysosomal degradation of the receptor together with the bound LDL-C. Current PCSK9 inhibitors are monoclonal antibodies that specifically absorb PCSK9. Subsequently, instead of being degraded the receptor can dissociate from LDL-C and recycle, consecutively resulting in an increased hepatocyte LDL receptor density and higher LDL-C clearance. In clinical trials, the PCSK9 inhibitors alirocumab and evolocumab induced reductions in LDL-C of up to 70 % in statin-treated as well as statin-naïve patients. So far, serious side effects (requiring cessation of drug treatment) occurred only in rare cases. Since this new class of lipid lowering drugs promises a high potential benefit, they have been approved by the EMA even before completion of the studies addressing clinically relevant endpoints like cardiovascular events and mortality. Therefore, the expected publication of these study results in 2017 may allow a better assessment of the efficacy and safety of PCSK9 inhibitors.

  5. Molecular biology of PCSK9: its role in LDL metabolism

    PubMed Central

    Horton, Jay D.; Cohen, Jonathan C.; Hobbs, Helen H.

    2009-01-01

    Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that destroys low density lipoprotein (LDL) receptors in liver and thereby controls the level of LDL in plasma. Mutations that increase PCSK9 activity cause hypercholesterolemia and coronary heart disease (CHD); mutations that inactivate PCSK9 have the opposite effect, lowering LDL levels and reducing CHD. Although the mechanism of PCSK9 action is not yet clear, the protease provides a new therapeutic target to lower plasma levels of LDL and prevent CHD. PMID:17215125

  6. Beneficial Effects of Berberine on Oxidized LDL-Induced Cytotoxicity to Human Retinal Müller Cells

    PubMed Central

    Fu, Dongxu; Yu, Jeremy Y.; Connell, Anna R.; Yang, Shihe; Hookham, Michelle B.; McLeese, Rebecca; Lyons, Timothy J.

    2016-01-01

    Purpose Limited mechanistic understanding of diabetic retinopathy (DR) has hindered therapeutic advances. Berberine, an isoquinolone alkaloid, has shown favorable effects on glucose and lipid metabolism in animal and human studies, but effects on DR are unknown. We previously demonstrated intraretinal extravasation and modification of LDL in human diabetes, and toxicity of modified LDL to human retinal Müller cells. We now explore pathogenic effects of modified LDL on Müller cells, and the efficacy of berberine in mitigating this cytotoxicity. Methods Confluent human Müller cells were exposed to in vitro–modified ‘highly oxidized, glycated (HOG-) LDL versus native-LDL (N-LDL; 200 mg protein/L) for 6 or 24 hours, with/without pretreatment with berberine (5 μM, 1 hour) and/or the adenosine monophosphate (AMP)-activated protein kinase (AMPK) inhibitor, Compound C (5 μM, 1 hour). Using techniques including Western blots, reactive oxygen species (ROS) detection assay, and quantitative real-time PCR, the following outcomes were assessed: cell viability (CCK-8 assay), autophagy (LC3, Beclin-1, ATG-5), apoptosis (cleaved caspase 3, cleaved poly-ADP ribose polymerase), oxidative stress (ROS, nuclear factor erythroid 2-related factor 2, glutathione peroxidase 1, NADPH oxidase 4), angiogenesis (VEGF, pigment epithelium-derived factor), inflammation (inducible nitric oxide synthase, intercellular adhesion molecule 1, IL-6, IL-8, TNF-α), and glial cell activation (glial fibrillary acidic protein). Results Native-LDL had no effect on cultured human Müller cells, but HOG-LDL exhibited marked toxicity, significantly decreasing viability and inducing autophagy, apoptosis, oxidative stress, expression of angiogenic factors, inflammation, and glial cell activation. Berberine attenuated all the effects of HOG-LDL (all P < 0.05), and its effects were mitigated by AMPK inhibition (P < 0.05). Conclusions Berberine inhibits modified LDL-induced Müller cell injury by activating

  7. Protocatechuic Acid Prevents oxLDL-Induced Apoptosis by Activating JNK/Nrf2 Survival Signals in Macrophages

    PubMed Central

    Varì, Rosaria; Scazzocchio, Beatrice; Santangelo, Carmela; Filesi, Carmelina; Galvano, Fabio; D'Archivio, Massimo; Masella, Roberta; Giovannini, Claudio

    2015-01-01

    Protocatechuic acid (PCA), one of the main metabolites of complex polyphenols, exerts numerous biological activities including antiapoptotic, anti-inflammatory, and antiatherosclerotic effects. Oxidised LDL have atherogenic properties by damaging arterial wall cells and inducing p53-dependent apoptosis in macrophages. This study was aimed at defining the molecular mechanism responsible for the protective effects of PCA against oxidative and proapoptotic damage exerted by oxLDL in J774 A.1 macrophages. We found that the presence of PCA in cells treated with oxLDL completely inhibited the p53-dependent apoptosis induced by oxLDL. PCA decreased oxLDL-induced ROS overproduction and in particular prevented the early increase of ROS. This decrease seemed to be the main signal responsible for maintaining the intracellular redox homeostasis hindering the activation of p53 induced by ROS, p38MAPK, and PKCδ. Consequently the overexpression of the proapoptotic p53-target genes such as p66Shc protein did not occur. Finally, we demonstrated that PCA induced the activation of JNK, which, in turn, determined the increase of nuclear Nrf2, leading to inhibition of the early ROS overproduction. We concluded that the antiapoptotic mechanism of PCA was most likely related to the activation of the JNK-mediated survival signals that strengthen the cellular antioxidant defences rather than to the PCA antioxidant power. PMID:26180584

  8. Improved volume-averaged model for steady and pulsed-power electronegative discharges

    SciTech Connect

    Kim, Sungjin; Lieberman, M. A.; Lichtenberg, A. J.; Gudmundsson, J. T.

    2006-11-15

    An improved volume-averaged global model is developed for a cylindrical (radius R, length L) electronegative (EN) plasma that is applicable over a wide range of electron densities, electronegativities, and pressures. It is applied to steady and pulsed-power oxygen discharges. The model incorporates effective volume and surface loss factors for positive ions, negative ions, and electrons combining three electronegative discharge regimes: a two-region regime with a parabolic EN core surrounded by an electropositive edge, a one-region parabolic EN plasma, and a one-region flat-topped EN plasma, spanning the plasma parameters and gas pressures of interest for low pressure processing (below a few hundred millitorr). Pressure-dependent effective volume and surface loss factors are also used for the neutral species. A set of reaction rate coefficients, updated from previous model calculations, is developed for oxygen for the species O{sub 2}, O{sub 2}({sup 1}{delta}{sub g}), O, O{sub 2}{sup +}, O{sup +}, and O{sup -}, based on the latest published cross-section sets and measurements. The model solutions yield all of the quantities above together with such important processing quantities such as the neutral/ion flux ratio {gamma}{sub O}/{gamma}{sub i}, with the discharge aspect ratio 2R/L and pulsed-power period and duty ratio (pulse on-time/pulse period) as parameters. The steady discharge results are compared to an experiment, giving good agreement. For steady discharges, increasing 2R/L from 1 to 6 leads to a factor of 0.45 reduction in {gamma}{sub O}/{gamma}{sub i}. For pulsed discharges with a fixed duty ratio, {gamma}{sub O}/{gamma}{sub i} is found to have a minimum with respect to pulse period. A 25% duty ratio pulse reduces {gamma}{sub O}/{gamma}{sub i} by a factor of 0.75 compared to the steady-state case.

  9. Associations between oxidized LDL to LDL ratio, HDL and vascular calcification in the feet of hemodialysis patients.

    PubMed

    An, Won Suk; Kim, Seong-Eun; Kim, Ki-Hyun; Bae, Hae-Rahn; Rha, Seo-Hee

    2009-01-01

    Cardiovascular mortality is associated with vascular calcification (VC) in hemodialysis (HD) patients. The present study was designed to find factors related with medial artery calcification on the plain radiography of feet by comparing C-reactive protein (CRP), plasminogen activator inhibitor type 1 (PAI-1) and lipid profile including oxidized low density lipoprotein (ox-LDL) and to elucidate associations among these factors in HD patients. Forty-eight HD patients were recruited for this study. VC in the feet was detected in 18 patients (37.5%) among total patients and 12 patients (85.7%) among diabetic patients. Diabetes, cardiovascular disease (CVD), pulse pressure, ox-LDL/LDL were higher and high density lipoprotein (HDL) was lower in patients with VC than in patients without VC. Negative associations were found between HDL and CRP, PAI-1. PAI-1 had positive association with ox-LDL/LDL. History of CVD was the only determinant of vascular calcification on the plain radiography of feet. Ox-LDL/LDL, HDL, CRP, and PAI-1 were closely related with one another in HD patients. History of CVD is the most important factor associated with the presence of VC and low HDL and relatively high oxidized LDL/LDL ratio may affect VC formation on the plain radiography in the feet of HD patients.

  10. An improved model to analyze Langmuir probe assisted photo-detachment signal for measuring electronegative plasma parameters

    NASA Astrophysics Data System (ADS)

    Sirse, Nishant; Oudini, Noureddine; Bendib, Abderrezeg; Ellingboe, Albert R.

    2016-09-01

    A diagnostic technique for measuring negative ion parameters based on Langmuir probe assisted laser photo-detachment relies on a theoretical model which relates the rise in the electron saturation current to electronegativity in the plasma. The existing model depend on various assumptions and neglect electrostatic potential barrier formed between the laser column (electropositive column) and the surrounding electronegative plasma in order to prevent the outward flow of electrons from the electropositive plasma column. These assumptions leads to erroneous estimation of the plasma electronegativity. In the present work, we present an analytical model to analyze Langmuir probe assisted photo-detachment signal in order to improve the accuracy of measured electronegativity and extended this technique for measuring electron temperature and charged species density. The analytical model is validated using both experiments and particle-in-cell simulation. The results shows improved accuracy in the measured parameters when compared to existing model. This work was supported by the Korea Institute for the Advancement of Technology and Ministry of Knowledge Economy (L-2010-1438-000), Republic of Korea, Enterprise Ireland and the European Regional Development Fund (ERDF) under NSRF 2007-2013.

  11. The Electronegativity Analysis of c-C4F8 as a Potential Insulation Substitute of SF6

    NASA Astrophysics Data System (ADS)

    Zhao, Xiaoling; Jiao, Juntao; Li, Bing; Xiao, Dengming

    2016-03-01

    The density distributions related to gas electronegativity for c-C4F8 gas, including negative ion, electron number and electron energy densities in the discharge process, are derived theoretically in both plane-to-plane and point-to-plane electrode geometries. These calculations have been performed through the Boltzmann equation in the condition of a steady-state Townsend (SST) experiment and a fluid model in the condition of both uniform and non-uniform electric fields. The electronegativity coefficients a = n-/ne of c-C4F8 and SF6 are compared to further describe the electron affinity of c-C4F8. The result shows that c-C4F8 represents an obvious electron-attachment performance in the discharge process. However, c-C4F8 still has much weaker gas electronegativity than SF6, whose electronegativity coefficient is lower than that of SF6 by at least three orders of magnitude. supported by National Natural Science Foundation of China (No. 51337006)

  12. A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function.

    PubMed

    Gao, Feng; Ihn, Hansel E; Medina, Marisa W; Krauss, Ronald M

    2013-04-01

    A common synonymous single nucleotide polymorphism in exon 12 of the low-density lipoprotein receptor (LDLR) gene, rs688, has been associated with increased plasma total and LDL cholesterol in several populations. Using immortalized lymphoblastoid cell lines from a healthy study population, we confirmed an earlier report that the minor allele of rs688 is associated with increased exon 12 alternative splicing (P < 0.05) and showed that this triggered nonsense-mediated decay (NMD) of the alternatively spliced LDLR mRNA. However, since synonymous single nucleotide polymorphisms may influence structure and function of the encoded proteins by co-translational effects, we sought to test whether rs688 was also functional in the full-length mRNA. In HepG2 cells expressing LDLR cDNA constructs engineered to contain the major or minor allele of rs688, the latter was associated with a smaller amount of LDLR protein at the cell surface (-21.8 ± 0.6%, P = 0.012), a higher amount in the lysosome fraction (+25.7 ± 0.3%, P = 0.037) and reduced uptake of fluorescently labeled LDL (-24.3 ± 0.7%, P < 0.01). Moreover, in the presence of exogenous proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces cellular LDL uptake by promoting lysosomal degradation of LDLR, the minor allele resulted in reduced capacity of a PCSK9 monoclonal antibody to increase LDL uptake. These findings are consistent with the hypothesis that rs688, which is located in the β-propeller region of LDLR, has effects on LDLR activity beyond its role in alternative splicing due to impairment of LDLR endosomal recycling and/or PCSK9 binding, processes in which the β-propeller is critically involved.

  13. The uremic toxin indoxyl sulfate acts as a pro- or antioxidant on LDL oxidation.

    PubMed

    Praschberger, M; Hermann, M; Wanner, J; Jirovetz, L; Exner, M; Kapiotis, S; Gmeiner, B M K; Laggner, H

    2014-06-01

    Uremic toxins have been shown to play a role in chronic kidney disease (CKD) associated oxidative stress. Oxidative stress and inflammation have been associated with increased risk of cardiovascular disease in uraemia. The oxidative modification of LDL may play a role in early atherogenesis. Enhanced LDL oxidation has been found in uremic patients which may account for accelerated atherosclerosis observed in CKD. The uremic toxin indoxyl sulfate (IS) has been reported to exert oxidative and antioxidative activity. Thus, in the present study we have investigated the influence of IS on the atherogenic modifications of LDL exposed in vitro to different oxidising systems. The transition metal ion (Cu(2+)) and hemin/H2O2 induced lipid oxidation reactions monitored by conjugated diene formation, were inhibited by the presence of IS, which points to possible antioxidant effects by this uremic toxin. A protective effect of IS on LDL apoprotein modification by the exposure to the product of the myeloperoxidase/H2O2/Cl(-) system HOCl, was also observed as estimated by protein carbonyl formation. In contrast, a marked increase in conjugated dienes and lipid hydroperoxides was observed when lipid oxidation was initiated by the free radical generator AAPH in presence of IS. The GC-MS analysis revealed the formation of indole-2,3-dione and 6,12-dihydro-6,12-dioxo-indolo[2,1-b]quinazoline (tryptanthrin) in IS/AAPH reaction. A scheme for the generation of tryptanthrin from IS via indoxyl radicals is proposed, which may facilitate LDL lipid oxidation. Our observations add further insight in the Janus-faced properties of this important uremic toxin.

  14. Regulation of hepatic LDL receptors by mTORC1 and PCSK9 in mice

    PubMed Central

    Ai, Ding; Chen, Chiyuan; Han, Seongah; Ganda, Anjali; Murphy, Andrew J.; Haeusler, Rebecca; Thorp, Edward; Accili, Domenico; Horton, Jay D.; Tall, Alan R.

    2012-01-01

    Individuals with type 2 diabetes have an increased risk of atherosclerosis. One factor underlying this is dyslipidemia, which in hyperinsulinemic subjects with early type 2 diabetes is typically characterized by increased VLDL secretion but normal LDL cholesterol levels, possibly reflecting enhanced catabolism of LDL via hepatic LDLRs. Recent studies have also suggested that hepatic insulin signaling sustains LDLR levels. We therefore sought to elucidate the mechanisms linking hepatic insulin signaling to regulation of LDLR levels. In WT mice, insulin receptor knockdown by shRNA resulted in decreased hepatic mTORC1 signaling and LDLR protein levels. It also led to increased expression of PCSK9, a known post-transcriptional regulator of LDLR expression. Administration of the mTORC1 inhibitor rapamycin caused increased expression of PCSK9, decreased levels of hepatic LDLR protein, and increased levels of VLDL/LDL cholesterol in WT but not Pcsk9–/– mice. Conversely, mice with increased hepatic mTORC1 activity exhibited decreased expression of PCSK9 and increased levels of hepatic LDLR protein levels. Pcsk9 is regulated by the transcription factor HNF1α, and our further detailed analyses suggest that increased mTORC1 activity leads to activation of PKCδ, reduced activity of HNF4α and HNF1α, decreased PCSK9 expression, and ultimately increased hepatic LDLR protein levels, which result in decreased circulating LDL levels. We therefore suggest that PCSK9 inhibition could be an effective way to reduce the adverse side effect of increased LDL levels that is observed in transplant patients taking rapamycin as immunosuppressive therapy. PMID:22426206

  15. Combined nonmetallic electronegativity equalisation and point-dipole interaction model for the frequency-dependent polarisability

    NASA Astrophysics Data System (ADS)

    Smalø, Hans S.; Åstrand, Per-Olof; Mayer, Alexandre

    2013-07-01

    A molecular mechanics model for the frequency-dependent polarisability is presented. It is a combination of a recent model for the frequency dependence in a charge-dipole model [Nanotechnology 19, 025203, 2008] and a nonmetallic modification of the electronegativity equalisation model rephrased as atom-atom charge-transfer terms [J. Chem. Phys. 131, 044101, 2009]. An accurate model for the frequency-dependent polarisability requires a more accurate partitioning into charge and dipole contributions than the static polarisability, which has resulted in several modifications of the charge-transfer model. Results are presented for hydrocarbons, including among others, alkanes, polyenes and aromatic systems. Although their responses to an electric field are quite different in terms of the importance of charge-transfer contributions, it is demonstrated that their frequency-dependent polarisabilities can be described with the same model and the same set of atom-type parameters.

  16. Propagation and oblique collision of ion-acoustic solitary waves in a magnetized dusty electronegative plasma

    SciTech Connect

    El-Labany, S. K.; Behery, E. E.; El-Shamy, E. F.

    2013-12-15

    The propagation and oblique collision of ion-acoustic (IA) solitary waves in a magnetized dusty electronegative plasma consisting of cold mobile positive ions, Boltzmann negative ions, Boltzmann electrons, and stationary positive/negative dust particles are studied. The extended Poincaré-Lighthill-Kuo perturbation method is employed to derive the Korteweg-de Vries equations and the corresponding expressions for the phase shifts after collision between two IA solitary waves. It turns out that the angle of collision, the temperature and density of negative ions, and the dust density of opposite polarity have reasonable effects on the phase shift. Clearly, the numerical results demonstrated that the IA solitary waves are delayed after the oblique collision. The current finding of this work is applicable in many plasma environments having negative ion species, such as D- and F-regions of the Earth's ionosphere and some laboratory plasma experiments.

  17. Small amplitude double layers in a warm electronegative plasma with trapped kappa distributed electrons

    NASA Astrophysics Data System (ADS)

    Shan, Shaukat Ali; Imtiaz, Nadia

    2017-06-01

    We employ quasipotential analysis to derive the Sagdeev potential which accounts for the effect of electron trapping in a warm electronegative plasma with κ-distributed electrons. The trapped electron density is truncated to some finite order of the electrostatic potential Φ. This consequently leads to an extended KdV equation which gives rise to small amplitude double layers (SIADLs). The effects of various plasma parameters, e.g., superthermality index, the electron trapping efficiency, the mass ratio of negative to positive ion, the number density ratio of electron to positive ion, and temperature ratio of positive ion to electron on the small amplitude ion acoustic double layers (SIADLs), have been investigated. It has been found that these parameters have a significant modifying role in the SIADLs.

  18. Relaxed states in electron-depleted electronegative dusty plasmas with two-negative ion species

    NASA Astrophysics Data System (ADS)

    Iqbal, M.; Iqbal

    2014-02-01

    The relaxation of an electron-depleted electronegative dusty plasma with two-negative ions is investigated. When the ratio of canonical vorticities to corresponding flows of all the plasma species is the same and all inertial and non-inertial forces are present, the relaxed state appears as a double Beltrami magnetic field which is the superposition of two force-free relaxed states. The numerical results show that highly diamagnetic relaxed magnetic fields can be obtained by controlling the flow and vorticities through a single Beltrami parameter. The study is useful to investigate the creation of diamagnetic plasma configurations which are considered to be very important in the context of nuclear fusion.

  19. Singularity and Bohm criterion in hot positive ion species in the electronegative ion sources

    SciTech Connect

    Aslaninejad, Morteza; Yasserian, Kiomars

    2016-05-15

    The structure of the discharge for a magnetized electronegative ion source with two species of positive ions is investigated. The thermal motion of hot positive ions and the singularities involved with it are taken into account. By analytical solution of the neutral region, the location of the singular point and also the values of the plasma parameter such as electric potential and ion density at the singular point are obtained. A generalized Bohm criterion is recovered and discussed. In addition, for the non-neutral solution, the numerical method is used. In contrast with cold ion plasma, qualitative changes are observed. The parameter space region within which oscillations in the density and potential can be observed has been scanned and discussed. The space charge behavior in the vicinity of edge of the ion sources has also been discussed in detail.

  20. On the electrophilic character of molecules through its relation with electronegativity and chemical hardness.

    PubMed

    Islam, Nazmul; Ghosh, Dulal C

    2012-01-01

    Electrophilicity is an intrinsic property of atoms and molecules. It probably originates logistically with the involvement in the physical process of electrostatics of soaked charge in electronic shells and the screened nuclear charge of atoms. Motivated by the existing view of conceptual density functional theory that similar to electronegativity and hardness equalization, there should be a physical process of equalization of electrophilicity during the chemical process of formation of hetero nuclear molecules, we have developed a new theoretical scheme and formula for evaluating the electrophilicity of hetero nuclear molecules. A comparative study with available bench marking reveals that the hypothesis of electrophilicity and equalization, and the present method of evaluating equalized electrophilicity, are scientifically promising.

  1. Influence of transition metal electronegativity on the oxygen storage capacity of perovskite oxides.

    PubMed

    Liu, Lu; Taylor, Daniel D; Rodriguez, Efrain E; Zachariah, Michael R

    2016-08-16

    The selection of highly efficient oxygen carriers (OCs) is a key step necessary for the practical development of chemical looping combustion (CLC). In this study, a series of ABO3 perovskites, where A = La, Ba, Sr, Ca and B = Cr, Mn, Fe, Co, Ni, Cu, are synthesized and tested in a fixed bed reactor for reactivity and stability as OCs with CH4 as the fuel. We find that the electronegativity of the transition metal on the B-site (λB), is a convenient descriptor for oxygen storage capacity (OSC) of our perovskite samples. By plotting OSC for total methane oxidation against λB, we observe an inverted volcano plot relationship. These results could provide useful guidelines for perovskite OC design and their other energy related applications.

  2. Dust acoustic shock wave in electronegative dusty plasma: Roles of weak magnetic field

    SciTech Connect

    Ghosh, Samiran; Ehsan, Z.; Murtaza, G.

    2008-02-15

    The effects of nonsteady dust charge variations and weak magnetic field on small but finite amplitude nonlinear dust acoustic wave in electronegative dusty plasma are investigated. The dynamics of the nonlinear wave are governed by a Korteweg-de Vries Burger equation that possesses dispersive shock wave. The weak magnetic field is responsible for the dispersive term, whereas nonsteady dust charge variation is responsible for dissipative term, i.e., the Burger term. The coefficient of dissipative term depends only on the obliqueness of the magnetic field. It is found that for parallel propagation the dynamics of the nonlinear wave are governed by the Burger equation that possesses monotonic shock wave. The relevances of the findings to cometary dusty plasma, e.g., Comet Halley are briefly discussed.

  3. On the Electrophilic Character of Molecules Through Its Relation with Electronegativity and Chemical Hardness

    PubMed Central

    Islam, Nazmul; Ghosh, Dulal C.

    2012-01-01

    Electrophilicity is an intrinsic property of atoms and molecules. It probably originates logistically with the involvement in the physical process of electrostatics of soaked charge in electronic shells and the screened nuclear charge of atoms. Motivated by the existing view of conceptual density functional theory that similar to electronegativity and hardness equalization, there should be a physical process of equalization of electrophilicity during the chemical process of formation of hetero nuclear molecules, we have developed a new theoretical scheme and formula for evaluating the electrophilicity of hetero nuclear molecules. A comparative study with available bench marking reveals that the hypothesis of electrophilicity and equalization, and the present method of evaluating equalized electrophilicity, are scientifically promising. PMID:22408445

  4. Electron attachment mass spectrometry as a diagnostics for electronegative gases and plasmas

    NASA Astrophysics Data System (ADS)

    Stoffels, E.; Stoffels, W. W.; Tachibana, K.

    1998-01-01

    Electron attachment mass spectrometry (EAMS) has been developed to study mixtures of electronegative gases and plasmas. A quadrupole mass spectrometer (QMS) has been used to detect negative ions, formed from sampled species by attachment of low energy electrons. Varying the electron energy allows to collect the attachment cross section of the considered species. EAMS appears to be a very powerful technique to study the chemistry of electronegative gases. Unlike ionization mass spectrometry, where cross sections are low at the threshold and rather flat over a broad range of electron energies, attachment resonances are sharp and distinct. Also very limited fragmentation of the parent negative ion occurs, so a given molecule yields only a few different negative ions. This facilitates identification of components in a gas mixture. It is particularly advantageous for detection of large, fragile molecules, which break up after ionization, but can be easily transformed into large negative ions. Moreover, sensitive detection of active species is possible due to their relatively high attachment cross sections. A particularly important application of EAMS is the determination of an effective attachment cross section in a plasma. Recording this cross section allows to decide on the actual negative ion formation mechanism in the plasma environment, where active products of plasma conversion can significantly alter the negative ion production channels and consequently the whole balance of charged particles. Examples of EAMS applications to fluorocarbon gases and low-pressure radio-frequency plasmas are discussed. In a CF4 discharge conversion of the parent gas into species like C2F6 and C3F8 is easily visualized. The dominant mechanism of negative ion formation in the plasma is electron attachment to these minority species and not to the parent gas. Also larger polymers are readily formed in fluorocarbon plasmas. In a C2F6 discharge molecules with up to ten carbon atoms (the

  5. Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism

    PubMed Central

    Strong, Alanna; Ding, Qiurong; Edmondson, Andrew C.; Millar, John S.; Sachs, Katherine V.; Li, Xiaoyu; Kumaravel, Arthi; Wang, Margaret Ye; Ai, Ding; Guo, Liang; Alexander, Eric T.; Nguyen, David; Lund-Katz, Sissel; Phillips, Michael C.; Morales, Carlos R.; Tall, Alan R.; Kathiresan, Sekar; Fisher, Edward A.; Musunuru, Kiran; Rader, Daniel J.

    2012-01-01

    Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans. PMID:22751103

  6. Induction of DKK1 by ox-LDL negatively regulates intracellular lipid accumulation in macrophages.

    PubMed

    Zhang, Yu; Ge, Cheng; Wang, Lin; Liu, Xinxin; Chen, Yifei; Li, Mengmeng; Zhang, Mei

    2015-01-02

    Dickkopf1 (DKK1), a canonical Wnt/β-catenin pathway antagonist, is closely associated with cardiovascular disease and adipogenesis. We performed an in vitro study to determine whether oxidized low-density lipoprotein (ox-LDL) increased the expression of DKK1 in macrophages and whether β-catenin and liver X receptor α (LXRα) were involved in this regulation. Induction of DKK1 expression by ox-LDL decreased the level of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) via a Wnt/β-catenin pathway and increased ATP-binding cassette transporter A/G1 (ABCA/G1) levels via a signal transducer and activator of transcription 3 (STAT3) pathway. Lower LOX-1 and higher ABCA/G1 levels inhibited cholesterol loading in macrophages. In conclusion, ox-LDL may induce DKK1 expression in macrophages to inhibit the accumulation of lipids through a mechanism that involves downregulation of LOX-1-mediated lipid uptake and upregulation of ABCA/G1-dependent cholesterol efflux.

  7. Tracking the Effect of Adatom Electronegativity on Systematically Modified AlGaN/GaN Schottky Interfaces.

    PubMed

    Reiner, Maria; Pietschnig, Rudolf; Ostermaier, Clemens

    2015-10-21

    The influence of surface modifications on the Schottky barrier height for gallium nitride semiconductor devices is frequently underestimated or neglected in investigations thereof. We show that a strong dependency of Schottky barrier heights for nickel/aluminum-gallium nitride (0001) contacts on the surface terminations exists: a linear correlation of increasing barrier height with increasing electronegativity of superficial adatoms is observed. The negatively charged adatoms compete with the present nitrogen over the available gallium (or aluminum) orbital to form an electrically improved surface termination. The resulting modification of the surface dipoles and hence polarization of the surface termination causes observed band bending. Our findings suggest that the greatest Schottky barrier heights are achieved by increasing the concentration of the most polarized fluorine-gallium (-aluminum) bonds at the surface. An increase in barrier height from 0.7 to 1.1 eV after a 15% fluorine termination is obtained with ideality factors of 1.10 ± 0.05. The presence of surface dipoles that are changing the surface energy is proven by the sessile drop method as the electronegativity difference and polarization influences the contact angle. The extracted decrease in the Lifshitz-van-der-Waals component from 48.8 to 40.4 mJ/m(2) with increasing electronegativity and concentration of surface adatoms confirms the presence of increasing surface dipoles: as the polarizability of equally charged anions decreases with increasing electronegativity, the diiodomethane contact angles increase significantly from 14° up to 39° after the 15% fluorine termination. Therefore, a linear correlation between increasing anion electronegativity of the (Al)GaN termination and total surface energy within a 95% confidence interval is obtained. Furthermore, our results reveal a generally strong Lewis basicity of (Al)GaN surfaces explaining the high chemical inertness of the surfaces.

  8. Novel model of negative secondary ion formation and its use to refine the electronegativity of almost fifty elements.

    PubMed

    Wittmaack, Klaus

    2014-06-17

    This study aimed to examine the recently proposed idea that the ionic contribution to atomic bonds is essential in determining the charge state of sputtered atoms. Use was made of negative secondary ion yields reported by Wilson for a large number of elements implanted in silicon and then sputter profiled by Cs bombardment. The derived normalized ion yields (or fractions) P vary by 6 orders of magnitude, but the expected exponential dependence on the electron affinity EA is evident only vaguely. Remarkably, a correlation of similar quality is observed if the data are presented as a function of the ionization potential IP. With IP being the dominant (if not sole) contributor to the electronegativity χ, one is led to assume that P depends on the sum χ + EA. About 72% of the "nonsaturated" ion yields are in accordance with a dependence of the form P ∝ exp[(χ + EA)/ε], with ε ≅ 0.2 eV, provided the appropriate value of χ is selected from the electronegativity tables of Pauling (read in eV), Mulliken or Allen. However, each of the three sources contributes only about one-third to the favorable electronegativity data. This unsatisfactory situation initiated the idea to derive the "true" electronegativity χSIMS from the measured ion yields P(χ + EA), verified for 48 elements. Significant negative deviations of χSIMS from a smooth increase with increasing atomic number are evident for elements with special outer-shell electron configurations such as (n-1)d(g-1)ns(1) or (n-1)d(10)ns(2)np(1). The results strongly support the new model of secondary ion formation and provide means for refining electronegativity data.

  9. Known players, new interplay in atherogenesis: Chronic shear stress and carbamylated-LDL induce and modulate expression of atherogenic LR11 in human coronary artery endothelium.

    PubMed

    Bajari, Tarek M; Winnicki, Wolfgang; Gensberger, Eva-Theres; Scharrer, Susanna I; Regele, Heinz; Aumayr, Klaus; Kopecky, Chantal; Gmeiner, Bernhard M; Hermann, Marcela; Zeillinger, Robert; Sengölge, Gürkan

    2014-02-01

    In this study we examined whether low-density lipoprotein (LDL) receptor family members represent a link between blood flow characteristics and modified low-density lipoproteins involved in endothelial injury, a pivotal factor in atherogenesis. We demonstrated the expression of pro-atherogenic LDL receptor relative (LR11) for the first time in human coronary artery endothelial cells (HCAEC) in vitro and in vivo. Next, LR11 expression and regulation were explored in HCAEC cultured conventionally or on the inner surface of hollow fiber capillaries under exposure to shear stress for 10 days in the presence or absence of LDL. There was no LR11 expression under static conditions. When exposed to chronic low shear stress (2.5 dynes/cm²) transmembrane and soluble endothelial-LR11 were detected in high levels irrespective of the type of LDL added (carbamylated or native). In contrast, chronic high shear stress (25 dynes/cm²) inhibited the LR11-inducing effect of LDL such that transmembrane and soluble LR11 expression became non-detectable with native LDL. Carbamylated LDL significantly counteracted this atheroprotective effect of high shear stress as shown by lower, yet sustained expression of soluble and transmembrane LR11. Oxidised LDL showed similar effects compared to carbamylated LDL but caused significantly lower LR11 expression under chronic high shear stress. Medium from HCAEC under LR11-inducing conditions enhanced vascular smooth muscle cell migration, which was abrogated by the anti-LR11 antibody. Expression of LR11 depended entirely on p38MAPK phosphorylation. We conclude that coronary endothelial LR11 expression modulated by LDL and chronic shear stress contributes to atherogenesis. LR11 and p38MAPK are potential targets for prevention of atherosclerosis.

  10. NF-kB activity-dependent P-selectin involved in ox-LDL-induced foam cell formation in U937 cell.

    PubMed

    Wang, Yi; Wang, Xiang; Sun, Minghui; Zhang, Zhenyu; Cao, Heng; Chen, Xiaoqing

    2011-08-05

    Oxidized low-density lipoprotein (ox-LDL) plays a critical role in regulation of atherosclerosis. However, little is known about the role of Nuclear factor kB (NF-kB) activity-dependent P-selectin in ox-LDL-induced foam cell formation during atherosclerosis. In this study, we first investigated ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. Treatment of U937 cells with ox-LDL increased lipid accumulation as well as intracellular cholesterol content. Next, a comparative analysis of gene expression profiling using cDNA microarray and Real-time-PCR indicated that ox-LDL exposure induced, in three treated groups, an extremely marked increase in the mRNA level of P-selectin. Protein levels of P-selectin and its upstream regulators IkBa and NF-kB showed that NF-kB pathway is involved in the ox-LDL-induced foam cell formation. Finally, overexpression of NF-kB significantly accelerated, whereas, inhibition of NF-kB with siRNA remarkably attenuated ox-LDL-induced macrophage-derived foam cell formation. It was concluded that the activity of NF-kB is augmented during macrophage-derived foam cell formation. Activation of NF-kB increased, whereas, inhibition of NF-kB decreased ox-LDL-induced P-selectin expression and lipid accumulation in macrophages, suggesting ox-LDL induced expression of P-selectin through degradation of IkBa and activation of NF-kB in the regulation of foam cell formation.

  11. NF-kB activity-dependent P-selectin involved in ox-LDL-induced foam cell formation in U937 cell

    SciTech Connect

    Wang, Yi; Wang, Xiang; Sun, Minghui; Zhang, Zhenyu; Cao, Heng; Chen, Xiaoqing

    2011-08-05

    Highlights: {yields} Ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. {yields} Ox-LDL induced expression of P-selectin through degradation of IkBa and augment of NF-kB activity and protein level during macrophage-derived foam cell formation. {yields} P-selectin and NF-kB may be identified as pivotal regulators of ox-LDL-induced foam cell formation. {yields} Therapy based on the inhibition of P-selectin and NF-kB may complement conventional treatments to prevent atherosclerosis. -- Abstract: Oxidized low-density lipoprotein (ox-LDL) plays a critical role in regulation of atherosclerosis. However, little is known about the role of Nuclear factor kB (NF-kB) activity-dependent P-selectin in ox-LDL-induced foam cell formation during atherosclerosis. In this study, we first investigated ox-LDL induced foam cell formation in the human U937 promonocytic cell line in a dose- and time-dependent manner. Treatment of U937 cells with ox-LDL increased lipid accumulation as well as intracellular cholesterol content. Next, a comparative analysis of gene expression profiling using cDNA microarray and Real-time-PCR indicated that ox-LDL exposure induced, in three treated groups, an extremely marked increase in the mRNA level of P-selectin. Protein levels of P-selectin and its upstream regulators IkBa and NF-kB showed that NF-kB pathway is involved in the ox-LDL-induced foam cell formation. Finally, overexpression of NF-kB significantly accelerated, whereas, inhibition of NF-kB with siRNA remarkably attenuated ox-LDL-induced macrophage-derived foam cell formation. It was concluded that the activity of NF-kB is augmented during macrophage-derived foam cell formation. Activation of NF-kB increased, whereas, inhibition of NF-kB decreased ox-LDL-induced P-selectin expression and lipid accumulation in macrophages, suggesting ox-LDL induced expression of P-selectin through degradation of IkBa and activation of NF-kB in the

  12. Dietary palmitic acid influences LDL-mediated lymphocyte proliferation differently to other mono- and polyunsaturated fatty acids in rats.

    PubMed

    Tinahones, F J; Gómez-Zumaquero, J M; Monzón, A; Rojo-Martínez, G; Pareja, A; Morcillo, S; Cardona, F; Olveira, G; Soriguer, F

    2004-10-01

    Recent studies suggest that the biological effects of saturated fatty acids depend on the length of their chain. We compared the effect of diets containing different fatty acids on plasma lipids and lymphocyte proliferation in the presence of lovastatin and with increasing amounts of LDL. Lymphocytes from rats fed with a diet rich in palmitic acid had a greater lymphocyte proliferation capacity than those from rats fed with diets rich in oleic acid, linoleic acid, or fish oil. This effect was maintained when small amounts of polyunsaturatwed fatty acids (PUFA; sunflower oil) were added to the palmitic acid diet. LDL receptor activity, measured by the capacity of lovastatin to revert the inhibition of lymphocyte proliferation with increasing amounts of LDL in the medium, was greater in the rats fed with palmitic acid, and was similar to the other groups when small amounts of PUFA were added. All the groups had similar levels of plasma cholesterol, but the LDL levels were significantly lower in the group fed with palmitic acid plus PUFA. The highest HDL-cholesterol (HDLc) levels were found in the palmitic acid group and the lowest LDL-cholesterol (LDLc)/HDLc ratio in the palmitic acid plus PUFA group. These results suggest that diets rich in palmitic acid do not raise total cholesterol, but reduce LDLc or keep it normal, and raise HDLc levels. This effect may be partly due to an increase in LDL receptor activity. The inclusion of small amounts of PUFA in the diet rich in palmitic acid substantially modified the LDL receptor response in the lymphocytes, suggesting that the proportion of different families of dietary fatty acids may be more important than the individual amount of each in absolute terms to explain their effects on plasma lipids and lipoproteins.

  13. Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation.

    PubMed

    Perségol, L; Vergès, B; Foissac, M; Gambert, P; Duvillard, L

    2006-06-01

    In healthy normolipidaemic and normoglycaemic control subjects, HDL are able to reverse the inhibition of vasodilation that is induced by oxidised LDL. In type 2 diabetic patients, HDL are glycated and more triglyceride-rich than in control subjects. These alterations are likely to modify the capacity of HDL to reverse the inhibition of vasodilation induced by oxidised LDL. Using rabbit aorta rings, we compared the ability of HDL from 16 type 2 diabetic patients and 13 control subjects to suppress the inhibition of vasodilation that is induced by oxidised LDL. Oxidised LDL inhibited endothelium-dependent vasodilation (maximal relaxation [Emax] = 58.2+/-14.6 vs 99.3+/-5.2% for incubation without any lipoprotein, p < 0.0001). HDL from control subjects significantly reduced the inhibitory effect of oxidised LDL on vasodilatation (Emax = 77.6+/-12.9 vs 59.5+/-7.7%, p < 0.001), whereas HDL from type 2 diabetic patients had no effect (Emax = 52.4+/-20.4 vs 57.2+/-18.7%, NS). HDL triglyceride content was significantly higher in type 2 diabetic patients than in control subjects (5.3+/-2.2 vs 3.1+/-1.4%, p < 0.01) and was highly inversely correlated to Emax for oxidised LDL+HDL in type 2 diabetic patients (r = -0.71, p < 0.005). In type 2 diabetes mellitus, the ability of HDL to counteract the inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL is impaired and is inversely correlated with HDL triglyceride content. These findings suggest that HDL are less atheroprotective in type 2 diabetic patients than in control subjects.

  14. An antibody against the C-terminal domain of PCSK9 lowers LDL cholesterol levels in vivo.

    PubMed

    Schiele, Felix; Park, John; Redemann, Norbert; Luippold, Gerd; Nar, Herbert

    2014-02-20

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with autosomal dominant hypercholesterolemia, a state of elevated levels of LDL (low-density lipoprotein) cholesterol. Autosomal dominant hypercholesterolemia can result in severe implications such as stroke and coronary heart disease. The inhibition of PCSK9 function by therapeutic antibodies that block interaction of PCSK9 with the epidermal growth factor-like repeat A domain of LDL receptor (LDLR) was shown to successfully lower LDL cholesterol levels in clinical studies. Here we present data on the identification, structural and biophysical characterization and in vitro and in vivo pharmacology of a PCSK9 antibody (mAb1). The X-ray structure shows that mAb1 binds the module 1 of the C-terminal domain (CTD) of PCSK9. It blocks access to an area bearing several naturally occurring gain-of-function and loss-of-function mutations. Although the antibody does not inhibit binding of PCSK9 to epidermal growth factor-like repeat A, it partially reverses PCSK9-induced reduction of the LDLR and LDL cholesterol uptake in a cellular assay. mAb1 is also effective in lowering serum levels of LDL cholesterol in cynomolgus monkeys in vivo. Complete loss of PCSK9 is associated with insufficient liver regeneration and increased risk of hepatitis C infections. Blocking of the CTD is sufficient to partially inhibit PCSK9 function. Antibodies binding the CTD of PCSK9 may thus be advantageous in patients that do not tolerate complete inhibition of PCSK9.

  15. LDL and HDL subfractions, dysfunctional HDL: treatment options.

    PubMed

    Garcia-Rios, Antonio; Nikolic, Dragana; Perez-Martinez, Pablo; Lopez-Miranda, Jose; Rizzo, Manfredi; Hoogeveen, Ron C

    2014-01-01

    Low-density lipoproteins (LDL) are considered as important risk factors for cardiovascular diseases (CVD), while highdensity lipoproteins (HDL) are well recognized for their putative role in reverse cholesterol transport and other atheroprotective functions. Both LDL and HDL are heterogeneous in nature, including various subfractions depending on the method of isolation (≥ 7 LDL and 10 HDL subspecies, respectively). While it is established that small, dense LDL (sdLDL) have atherogenic potential, the role of different HDL subfractions is still largely unclear. The majority of clinical studies suggest an atheroprotective role of larger HDL particles, although recent work has highlighted the role of dysfunctional HDL within different subfractions. Several therapeutic approaches are able to primarily target cholesterol concentration in LDL or HDL. Certain drugs, such as niacin, statins and fibrates target multiple lipid traits (i.e. pleiotropic drug effects), while cholesterol ester transfer protein (CETP) inhibitors are able to increase plasma HDL cholesterol levels. Statins represent the most used lipid-lowering drugs, but there is a continued interest in the development of novel therapeutic approaches, including those that might affect dysfunctional HDL. Targeting distinct LDL and HDL subfractions may potentially reduce the residual risk seen in clinical endpoint trials.

  16. OxLDL-targeted iron oxide nanoparticles for in vivo MRI detection of perivascular carotid collar induced atherosclerotic lesions in ApoE-deficient mice

    PubMed Central

    Wen, Song; Liu, Dong-Fang; Liu, Zhen; Harris, Steven; Yao, Yu-Yu; Ding, Qi; Nie, Fang; Lu, Tong; Chen, Hua-Jun; An, Yan-Li; Zang, Feng-Chao; Teng, Gao-Jun

    2012-01-01

    Atherosclerotic disease is a leading cause of morbidity and mortality in developed countries, and oxidized LDL (OxLDL) plays a key role in the formation, rupture, and subsequent thrombus formation in atherosclerotic plaques. In the current study, anti-mouse OxLDL polyclonal antibody and nonspecific IgG antibody were conjugated to polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles, and a carotid perivascular collar model in apolipoprotein E-deficient mice was imaged at 7.0 Tesla MRI before contrast administration and at 8 h and 24 h after injection of 30 mg Fe/kg. The results showed MRI signal loss in the carotid atherosclerotic lesions after administration of targeted anti-OxLDL-USPIO at 8 h and 24 h, which is consistent with the presence of the nanoparticles in the lesions. Immunohistochemistry confirmed the colocalization of the OxLDL/macrophages and iron oxide nanoparticles. The nonspecific IgG-USPIO, unconjugated USPIO nanoparticles, and competitive inhibition groups had limited signal changes (p < 0.05). This report shows that anti-OxLDL-USPIO nanoparticles can be used to directly detect OxLDL and image atherosclerotic lesions within 24 h of nanoparticle administration and suggests a strategy for the therapeutic evaluation of atherosclerotic plaques in vivo. PMID:22393161

  17. Differential regulation of acid sphingomyelinase in macrophages stimulated with oxidized low-density lipoprotein (LDL) and oxidized LDL immune complexes: role in phagocytosis and cytokine release.

    PubMed

    Truman, Jean-Philip; Al Gadban, Mohammed M; Smith, Kent J; Jenkins, Russell W; Mayroo, Nalini; Virella, Gabriel; Lopes-Virella, Maria F; Bielawska, Alicja; Hannun, Yusuf A; Hammad, Samar M

    2012-05-01

    Oxidized low-density lipoprotein (oxLDL) and oxLDL-containing immune complexes (oxLDL-IC) contribute to the formation of lipid-laden macrophages (foam cells). Fcγ receptors mediate uptake of oxLDL-IC, whereas scavenger receptors internalize oxLDL. We have previously reported that oxLDL-IC, but not free oxLDL, activate macrophages and prolong their survival. Sphingomyelin is a major constituent of cell membranes and lipoprotein particles and acid sphingomyelinase (ASMase) hydrolyses sphingomyelin to generate the bioactive lipid ceramide. ASMase exists in two forms: lysosomal (L-ASMase) and secretory (S-ASMase). In this study we examined whether oxLDL and oxLDL-IC regulate ASMase differently, and whether ASMase mediates monocyte/macrophage activation and cytokine release. The oxLDL-IC, but not oxLDL, induced early and consistent release of catalytically active S-ASMase. The oxLDL-IC also consistently stimulated L-ASMase activity, whereas oxLDL induced a rapid transient increase in L-ASMase activity before it steadily declined below baseline. Prolonged exposure to oxLDL increased L-ASMase activity; however, activity remained significantly lower than that induced by oxLDL-IC. Further studies were aimed at defining the function of the activated ASMase. In response to oxLDL-IC, heat-shock protein 70B' (HSP70B') was up-regulated and localized with redistributed ASMase in the endosomal compartment outside the lysosome. Treatment with oxLDL-IC induced the formation and release of HSP70-containing and IL-1β-containing exosomes via an ASMase-dependent mechanism. Taken together, the results suggest that oxLDL and oxLDL-IC differentially regulate ASMase activity, and the pro-inflammatory responses to oxLDL-IC are mediated by prolonged activation of ASMase. These findings may contribute to increased understanding of mechanisms mediating macrophage involvement in atherosclerosis.

  18. Phthalocyanine-labeled LDL for tumor imaging and photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Li, Hui; Marotta, Diane; Kim, Soungkyoo; Chance, Britton; Glickson, Jerry D.; Busch, Theresa M.; Zheng, Gang

    2005-01-01

    Current limitation of both near-infrared (NIR) tumor imaging and photodynamic therapy (PDT) is their lack of sufficient tumor-to-tissue contrast due to the relatively non-specific nature of delivering dye to the tumor, which has led to false negatives for NIR imaging and inadequate therapeutic ratio for PDT. Hence, agents targeting "cancer signatures", i.e. molecules that accumulate selectively in cancer cells, are particular attractive. One of these signatures is low-density-lipoprotein receptor (LDLR), which is overexpressed in many tumors. We have developed pyropheophorbide cholesterol oleate reconstituted LDL as a LDLR-targeting photosensitizer (PS) and demonstrated its LDLR-mediated uptake in vitro and in vivo. To improve the labeling efficiency for achieving high probe/protein ratio, tetra-t-butyl silicon phthalocyanine bearing two oleate moieties at its axial positions, (tBu)4SiPcBOA, was designed and synthesized. This compound was designed to 1) prevent the PS aggregation; 2) improve the PS solubility in non-polar solvent; and 3) maximize the PS binding to LDL phospholipid monolayer. Using this novel strategy, (tBu)4SiPcBOA was reconstituted into LDL (r-SiPcBOA-LDL) with a very high payload (500:1 molar ratio). In addition, (tBu)4SiPcBOA reconstituted acetylated LDL (r-SiPcBOA)-AcLDL with similar payload was also prepared. Since Ac-LDL cannot bind to LDLR, (r-SiPcBOA)-AcLDL can serve as the negative control to evaluate LDLR targeting specificity. For biological evaluation of these new agents, confocal microscopy and in vitro PDT protocols were performed using LDLR-overexpressing human hepatoblastoma G2 (HepG2) tumor model. These studies suggest that LDL serves as a delivery vehicle to bring large amount of the NIR/PDT agents selectively to tumor cells overexpressing LDLR.

  19. Uptake and catabolism of modified LDL in scavenger-receptor class A type I/II knock-out mice.

    PubMed Central

    Van Berkel, T J; Van Velzen, A; Kruijt, J K; Suzuki, H; Kodama, T

    1998-01-01

    The liver is the major organ responsible for the uptake of modified low-density lipoprotein (LDL) from the blood circulation, with endothelial and Kupffer cells as major cellular uptake sites. Scavenger-receptors, which include various classes, are held responsible for this uptake. Mice deficient in scavenger-receptor class A types I and II were created and the fate of acetylated LDL (Ac-LDL) in vivo and its interaction with liver endothelial, Kupffer and peritoneal macrophages was characterized. Surprisingly, the decay in vivo (t12 < 2 min), tissue distribution and liver uptake (at 5 min it was 77.4 +/- 4.6% of the injected dose) of Ac-LDL in the knock-out mice were not significantly different from control mice (t12 < 2 min and liver uptake 79.1 +/- 4.6% of the injected dose). A separation of mice liver cells into parenchymal, endothelial and Kupffer cells 10 min after injection of Ac-LDL indicated that in both control and knock-out mice the liver endothelial cells were responsible for more than 70% of the liver uptake. Both in control and knock-out mice, preinjection of polyinosinic acid (poly I, 200 microg) completely blocked the liver uptake, indicating that both in control and knock-out mice the scavenger-receptors are sensitive to poly I. Preinjection of suboptimal poly I concentrations (20 and 50 microg) provided evidence that the serum decay and liver uptake of Ac-LDL is more readily inhibited in the knock-out mice as compared with the control mice, indicating less efficient removal of Ac-LDL in vivo in the knock-out mice under these conditions. Studies in vitro with isolated liver endothelial and Kupffer cells from knock-out mice indicate that the cell association of Ac-LDL during 2 h at 37 degrees C is 50 and 53% of the control, respectively, whereas the degradation reaches values of 58 and 63%. For peritoneal macrophages from knock-out mice the cell association of Ac-LDL was identical to the control mice whereas the Ac-LDL degradation in cells from the

  20. Oxidized LDL, anti-oxidized LDL and anti-annexin A5 antibodies in primary antiphospholipid syndrome.

    PubMed

    Becarevic, Mirjana; Singh, Sandra; Majkic-Singh, Nada

    2008-01-01

    The aim of this study was to compare whether oxidized LDL (oxLDL), anti-oxLDL and anti-annexin (anx) A5 antibodies are associated with clinical features of primary antiphospholipid syndrome (PAPS), and to compare these to well-defined groups of non-PAPS myocardial infarction survivors (non-PAPS MI) and to non-PAPS patients with pulmonary emboli (non-PAPS PE). All parameters investigated were analyzed by ELISA using commercial reagents. PAPS patients with MI, in comparison to the group of non-PAPS MI survivors, had significantly elevated concentrations of oxLDL (p = 0.003) and anti-oxLDL antibodies (p = 0.024). Anti-anxA5 antibodies of the IgG isotype were associated with recurrent abortions (OR = 4.788, p = 0.036, 95% CI: 1.104 - 20.762). OxLDL and anti-oxLDL antibodies represent additional risk factors which, together with other factors, might lead to complications of arterial thromboses, such as myocardial infarctions in PAPS, while association of IgG anti-anxA5 antibodies with recurrent abortions is a reflection of the small number of patients with this feature involved in the study and should therefore be investigated further.

  1. Saikosaponin-a Attenuates Oxidized LDL Uptake and Prompts Cholesterol Efflux in THP-1 Cells.

    PubMed

    He, Dan; Wang, Hongyan; Xu, Ling; Wang, Xiaoqing; Peng, Kuang; Wang, Lili; Liu, Pixu; Qu, Peng

    2016-06-01

    Saikosaponins-a (Ssa) is a major bioactive extract of Radix Bupleuri which is a traditional Chinese medicine. The roles of inflammatory response and lipid transportation in the process of atherosclerosis have drawn increasing attention. We explored the regulation of lipid transportation and immune-inflammatory role of Ssa in early atherosclerosis. The antiatherogenic actions and possible molecular mechanisms of Ssa were texted in THP-1 cells. We examined the effect of Ssa on oxidized low-density lipoprotein (ox-LDL)-induced lipid uptake, cholesterol efflux, immune-inflammatory response. THP-1 macrophages were treated with Ssa followed by ox-LDL for 24 hours. Results from western blot showed that Ssa obviously reduced lipoprotein uptake to block foam cell formation and the expression of Density Lipoprotein Receptor-1 and CD36. Ssa also significantly boosted cholesterol efflux and the expression of ATP binding cassettetransporter A1 and peroxisome proliferator-activated receptor γ. The results also indicated that Ssa inhibited ox-LDL-induced activation of AKT and nuclear factor-κB, assembly of NLRP3 inflammasome and production of proinflammatory cytokines. It is suggested that the ability against immune inflammatory response of Ssa is due to modulation of the PI3K/AKT/NF-κB/NLRP3 pathway. In conclusion, this study provides new insight into Ssa's molecular mechanism and its therapeutic potential in the treatment of atherosclerosis.

  2. LDL biochemical modifications: a link between atherosclerosis and aging

    PubMed Central

    Alique, Matilde; Luna, Carlos; Carracedo, Julia; Ramírez, Rafael

    2015-01-01

    Atherosclerosis is an aging disease in which increasing age is a risk factor. Modified low-density lipoprotein (LDL) is a well-known risk marker for cardiovascular disease. High-plasma LDL concentrations and modifications, such as oxidation, glycosylation, carbamylation and glycoxidation, have been shown to be proatherogenic experimentally in vitro and in vivo. Atherosclerosis results from alterations to LDL in the arterial wall by reactive oxygen species (ROS). Evidence suggests that common risk factors for atherosclerosis raise the likelihood that free ROS are produced from endothelial cells and other cells. Furthermore, oxidative stress is an important factor in the induction of endothelial senescence. Thus, endothelial damage and cellular senescence are well-established markers for atherosclerosis. This review examines LDL modifications and discusses the mechanisms of the pathology of atherosclerosis due to aging, including endothelial damage and oxidative stress, and the link between aging and atherosclerosis. PMID:26637360

  3. 2013 Cholesterol Guidelines Revisited: Percent LDL Cholesterol Reduction or Attained LDL Cholesterol Level or Both for Prognosis?

    PubMed

    Bangalore, Sripal; Fayyad, Rana; Kastelein, John J; Laskey, Rachel; Amarenco, Pierre; DeMicco, David A; Waters, David D

    2016-04-01

    The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the treatment of blood cholesterol recommends moderate- to high-intensity statins for patients with atherosclerotic cardiovascular disease but departs from the traditional treat-to-target approach. Whether percent low-density lipoprotein cholesterol (LDL-C) reduction or attained LDL-C levels add incremental prognostic value to statin dose is not known. Patients in the Treating to New Targets (TNT), Incremental Decrease in Endpoints through Aggressive Lipid Lowering (IDEAL), and Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trials (patient-level data) randomized to a statin arm (atorvastatin 80 mg/10 mg or simvastatin 20 mg) were chosen. Patients were divided into groups based on attained LDL-C levels (≤70 vs >70 mg/dL) and percent LDL-C reduction (≥50% vs <50%). Primary outcome was major cardiovascular event defined as death due to coronary heart disease, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke. Incremental prognostic value was assessed by using a forward conditional Cox proportional hazards model. Two models were tested: Model 1: Step 1 statin dose; Step 2 add attained LDL-C levels (continuous variable); Step 3 add percent LDL-C reduction (continuous variable). Model 2: Steps 2 and 3 were reversed. Among 13,937 patients included in this study, percent LDL-C reduction added incremental prognostic value over both statin dose and attained LDL-C levels (global chi-square increased from 3.64 to 26.1 to 47.5; P <.0001). However, attained LDL-C level did not provide incremental prognostic value over statin dose and percent LDL-C reduction (global chi-square increased from 3.64 to 47.5 to 47.5; P <.0001 and .94, respectively). Among patients with attained LDL-C ≤70 mg/dL, those with percent LDL-C reduction of <50% had a significantly higher risk of primary outcome (hazard ratio [HR], 1.51; 95% confidence interval [CI

  4. Nox4 is a Novel Inducible Source of Reactive Oxygen Species in Monocytes and Macrophages and Mediates OxLDL-Induced Macrophage Death

    PubMed Central

    Lee, Chi Fung; Qiao, Mu; Schröder, Katrin; Zhao, Qingwei; Asmis, Reto

    2010-01-01

    Rationale The enhanced formation of intracellular reactive oxygen species (ROS) induced by oxidized low density lipoprotein (OxLDL) promotes macrophage death, a process likely to contribute to the formation of necrotic cores and the progression of atherosclerotic lesions. Yet macrophage deficiency of phagocytic NADPH oxidase (Nox2), the primary source of ROS in macrophages, does not reduce atherosclerotic lesion development in mice. This suggests an as yet unidentified NADPH oxidase may be present in macrophages and responsible for the intracellular ROS formation induced by OxLDL. Objective The aim of this study was to identify the source of intracellular ROS involved in macrophage death. Methods and Results Nox4 was expressed in human monocytes and mature macrophages, and was localized to the ER and to defined foci within the nucleus. Nox4 colocalized with p22phox, and both proteins were up-regulated in response to OxLDL stimulation, whereas Nox2/gp91phox levels remained unchanged. Induction of Nox4 expression, intracellular ROS formation and macrophage cytotoxicity induced by OxLDL were blocked by MEK1/2 inhibition, but not by inhibitors of p38-MAPK, JNK or JAK2. SiRNA knockdown of Nox4 inhibited both intracellular ROS production and macrophage cytotoxicity induced by OxLDL, while Nox4 over-expression enhanced both OxLDL-stimulated ROS formation and macrophage death. Conclusions Nox4 is a novel source of intracellular ROS in human monocytes and macrophages. Induction of Nox4 by OxLDL is mediated by the MEK1/ERK pathway and required for OxLDL cytotoxicity in human macrophages, implicating monocytic Nox4 in atherogenesis. PMID:20360249

  5. Two-dimensional modulated ion-acoustic excitations in electronegative plasmas

    NASA Astrophysics Data System (ADS)

    Panguetna, Chérif S.; Tabi, Conrad B.; Kofané, Timoléon C.

    2017-09-01

    Two-dimensional modulated ion-acoustic waves are investigated in an electronegative plasma. Through the reductive perturbation expansion, the governing hydrodynamic equations are reduced to a Davey-Stewartson system with two-space variables. The latter is used to study the modulational instability of ion-acoustic waves along with the effect of plasma parameters, namely, the negative ion concentration ratio (α) and the electron-to-negative ion temperature ratio (σn). A parametric analysis of modulational instability is carried out, where regions of plasma parameters responsible for the emergence of modulated ion-acoustic waves are discussed, with emphasis on the behavior of the instability growth rate. Numerically, using perturbed plane waves as initial conditions, parameters from the instability regions give rise to series of dromion solitons under the activation of modulational instability. The sensitivity of the numerical solutions to plasma parameters is discussed. Some exact solutions in the form one- and two-dromion solutions are derived and their response to the effect of varying α and σn is discussed as well.

  6. Sheath and boundary conditions in a collisional magnetized warm electronegative plasma

    SciTech Connect

    Li, Jing-ju; Ma, J. X.; Wei, Zi-an

    2013-06-15

    The characteristics of a weakly collisional sheath in a warm electronegative plasma in the presence of an oblique magnetic field are investigated using a fluid model including the effects of ionization and ion-neutral collisions. The general sheath criterion imposed on the entrance velocity component of the positive ions perpendicular to the wall at the sheath-presheath edge is derived and discussed. It is shown that the boundary conditions are crucial to the sheath structure. Without including the entrance velocity components parallel to the wall, a pulse-like structure in the positive-ion density distribution near the sheath-presheath edge appears if the magnetic field is strong. With inclusion of all velocity components at the edge, the pulse-like structure disappears, resulting in a smooth sheath profile. It is also found that increasing the temperature and decreasing the concentration of the negative ions will increase the sheath thickness, and increasing the magnetic field will decrease the sheath thickness.

  7. Modeling of the mutual molecular polarization with an electronegativity equalization approach

    SciTech Connect

    Gerwens, H.; Jug, K.

    1995-12-05

    A model for the mutual polarization of two approaching molecules is proposed, exploiting the principle of electronegativity equalization. The deformation of the electronic density of one molecule is the response to the perturbation of its chemical potential due to the electrostatic potential of the other molecule. The electronic densities, the density deformations, and the electrostatic potentials of both molecules are described with a previously developed asymptotic density model (ADM). The ADM model allows a partitioning of all relevant properties in terms of atomic quantities. The perturbation of the chemical potential is given in atomic resolution, and the change of the electronic density is represented in terms of atomic charges. A hardness tensor, which determines the changes of the atomic chemical potentials due to the changes of the atomic charges, is modeled consistently with the ADM and earlier approaches. The results of the model, the changes of atomic charges within the molecules due to their mutual interaction, are compared with the changes of atomic charges obtained from population analysis of ab initio calculations. 31 refs., 7 figs., 3 tabs.

  8. Discovery of Metabolically Stabilized Electronegative Polyacridine-PEG Peptide DNA Open Polyplexes

    PubMed Central

    Fernandez, Christian A.; Baumhover, Nicholas J.; Anderson, Kevin; Rice, Kevin G.

    2010-01-01

    Cationic condensing peptides and polymers bind electrostatically to DNA to form cationic polyplexes. While many cationic polyplexes are able to achieve in vitro transfection mediated through electrostatic interactions, few have been able to mediate gene transfer in vivo. The present study describes the development and testing of polyacridine PEG-peptides that bind to plasmid DNA by intercalation resulting in electronegative open polyplex DNA. Polyacridine PEG-peptides were prepared by chemically conjugating 6-(9-acridinylamino) hexanoic acid onto side chains of Lys in PEG-Cys-Trp-(Lys)3, 4, or 5. The resulting PEG-Cys-Trp-(Lys-(Acr))3, 4, or 5 peptides bound tightly to DNA by polyintercalation, rather than electrostatic binding. Unlike polycationic polyplexes, polyacridine PEG-peptide polyplexes were anionic and open coiled, as revealed by zeta potential and atomic force microscopy. PEG-Cys-Trp-(Lys-(Acr))5 showed the highest DNA binding affinity and the greatest ability to protect DNA from metabolism by DNase. Polyacridine PEG-peptide DNA open polyplexes were dosed intramuscularly and electroporated in mice to demonstrate their functional activity in gene transfer. These results establish polyacridine PEG-peptide DNA open polyplexes as a novel gene delivery method for in vivo use. PMID:20218669

  9. Universal method to calculate the stability, electronegativity, and hardness of dianions.

    PubMed

    von Szentpály, László

    2010-10-14

    The electronic stability of gas-phase dianions of arbitrary size, X(2-), is determined by the first universal method to calculate second electron affinities, A(2). The model expresses A(2,calc) = A(1) - (7/6)η(0) by the first electron affinity, A(1), and chemical hardness, η(0), of the neutral "grandparent" species. A comparison with 37 reference data of atoms, molecules, superatoms, and clusters yields A(2,ref) = 1.004A(2,calc) - 0.023 eV, with a mean unsigned deviation of MUD = 0.095 eV and a correlation coefficient of R = 0.9987. Predictions of second electron affinities are given for a further 24 species. The universality of the model is apparent from the broad variety of compounds formed by 30 diverse elements. The electronegativity and hardness of dianions are determined for the first time as χ(X(2-)) = A(2) and η(X(2-)) = (7/12)η(0), respectively. Pearson and Parr's operational assumption regarding the hardness of anionic bases for the hard-soft acid-base (HSAB) principle is rationalized, and predictions for hard and soft dianionic bases are presented. For trianions, first criteria and predictions for electronic stability are given and require A(1) > (7/4)η(0).

  10. Discovery of metabolically stabilized electronegative polyacridine-PEG peptide DNA open polyplexes.

    PubMed

    Fernandez, Christian A; Baumhover, Nicholas J; Anderson, Kevin; Rice, Kevin G

    2010-04-21

    Cationic condensing peptides and polymers bind electrostatically to DNA to form cationic polyplexes. While many cationic polyplexes are able to achieve in vitro transfection mediated through electrostatic interactions, few have been able to mediate gene transfer in vivo. The present study describes the development and testing of polyacridine PEG-peptides that bind to plasmid DNA by intercalation resulting in electronegative open polyplex DNA. Polyacridine PEG-peptides were prepared by chemically conjugating 6-(9-acridinylamino) hexanoic acid onto side chains of Lys in PEG-Cys-Trp-(Lys)(3, 4, or 5). The resulting PEG-Cys-Trp-(Lys-(Acr))(3, 4, or 5) peptides bound tightly to DNA by polyintercalation, rather than electrostatic binding. Unlike polycationic polyplexes, polyacridine PEG-peptide polyplexes were anionic and open coiled, as revealed by zeta potential and atomic force microscopy. PEG-Cys-Trp-(Lys-(Acr))(5) showed the highest DNA binding affinity and the greatest ability to protect DNA from metabolism by DNase. Polyacridine PEG-peptide DNA open polyplexes were dosed intramuscularly and electroporated in mice to demonstrate their functional activity in gene transfer. These results establish polyacridine PEG-peptide DNA open polyplexes as a novel gene delivery method for in vivo use.

  11. Global Model of Time-Modulated Electronegative Discharges for Neutral Radical and Electron Temperature Control

    NASA Astrophysics Data System (ADS)

    Kim, Sungjin; Lieberman, M. A.; Lichtenberg, A. J.

    2003-10-01

    Control and reduction of neutral radical flux/ion flux ratio and electron temperature Te is required for next generation etching in the microelectronics industry. We investigate time-modulated power for these purposes using a volume-averaged (global) oxygen discharge model, We consider pressures of 10-50 mTorr and plasma densities of 10^10-10^11 cm-3. In this regime, the discharge is found to be weakly electronegative. The modulation period and the duty ratio (on-time/period) are varied to determine the optimum conditions for reduction of FR= O-atom flux/ion flux and T_e. Two chambers with different height/diameter ratios (<< 1, and unity) are examined to determine the influence of the surface-area/volume ratio. At a fixed duty ratio, both FR and Te are found to have minimum values as the pulse period is varied, with the minimum value decreasing as the duty ratio decreases. Significant reductions in FR and Te are found. Support provided by Lam Research, NSF Grant ECS-0139956, California industries, and UC-SMART Contract SM99-10051.

  12. Formation of collisional sheath in electronegative plasma with two species of positive ions

    SciTech Connect

    Moulick, R. Goswami, K. S.

    2015-03-15

    Sheath formation is investigated for electronegative plasma in presence of two species of positive ions in collisional environment. The gas under consideration is a mixture of oxygen and argon. Argon is the considered as having fixed volume and impact of collision is studied with increasing pressure of oxygen. Fluid equations are solved for three species namely, the two positive ions and a negative ion. Electrons are considered to follow Boltzmann distribution. Collision is modeled by constant mean free path model and has been used as a parameter. It has been found that collision enhances the sheath formation. The negative ion core is nearly unaffected by the presence of collision and is governed by the electric potential. The negative flux field is, however, affected by the presence of collision and shows a steady behavior in front of the wall. The two positive ions are heavily affected by the presence of collision and the modeling is such that their equilibrium densities can be estimated by solving simultaneous cubic equations.

  13. Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

    SciTech Connect

    Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radi, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer

    2008-07-28

    Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 {angstrom} in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids.

  14. Extraction and neutralization of positive and negative ions from a pulsed electronegative inductively coupled plasma

    NASA Astrophysics Data System (ADS)

    Marinov, D.; el Otell, Z.; Bowden, M. D.; Braithwaite, N. St. J.

    2015-12-01

    Almost electron-free (ion-ion) plasmas can be transiently formed during the afterglow phase of pulsed plasmas in electronegative gases. In ion-ion plasmas, both positive and negative ions can be extracted which makes them advantageous for a number of applications. In this paper, we investigate the extraction and acceleration of positive and negative ion beams from a pulsed inductively coupled plasma in SF6. The plasma is bounded by two electrodes biased synchronously with the discharge modulation. It is shown that when a DC bias voltage is applied during the afterglow phase, positive/negative ions are accelerated in a positive/negative space charge sheath formed in front of one of the electrodes. The energy of extracted ions closely follows the amplitude of the applied bias voltage (25-150 V) and the peak beam current density reaches 2 A m-2. With a view to using the described system as a source of energetic neutral beams for low damage material processing, simultaneous extraction and surface neutralization of positive and negative ions using an extraction electrode with high aspect ratio apertures is investigated.

  15. New CETP inhibitor K-312 reduces PCSK9 expression: a potential effect on LDL cholesterol metabolism.

    PubMed

    Miyosawa, Katsutoshi; Watanabe, Yuichiro; Murakami, Kentaro; Murakami, Takeshi; Shibata, Haruki; Iwashita, Masaya; Yamazaki, Hiroyuki; Yamazaki, Koichi; Ohgiya, Tadaaki; Shibuya, Kimiyuki; Mizuno, Ken; Tanabe, Sohei; Singh, Sasha A; Aikawa, Masanori

    2015-07-15

    Despite significant reduction of cardiovascular events by statin treatment, substantial residual risk persists, driving emerging needs for the development of new therapies. We identified a novel cholesteryl ester transfer protein (CETP) inhibitor, K-312, that raises HDL and lowers LDL cholesterol levels in animals. K-312 also suppresses hepatocyte expression of proprotein convertase subtilisin/kexin 9 (PCSK9), a molecule that increases LDL cholesterol. We explored the underlying mechanism for the reduction of PCSK9 expression by K-312. K-312 inhibited in vitro human plasma CETP activity (IC50; 0.06 μM). Administration of K-312 to cholesterol-fed New Zealand White rabbits for 18 wk raised HDL cholesterol, decreased LDL cholesterol, and attenuated aortic atherosclerosis. Our search for additional beneficial characteristics of this compound revealed that K-312 decreases PCSK9 expression in human primary hepatocytes and in the human hepatoma cell line HepG2. siRNA silencing of CETP in HepG2 did not compromise the suppression of PCSK9 by K-312, suggesting a mechanism independent of CETP. In HepG2 cells, K-312 treatment decreased the active forms of sterol regulatory element-binding proteins (SREBP-1 and -2) that regulate promoter activity of PCSK9. Chromatin immunoprecipitation assays demonstrated that K-312 decreased the occupancy of SREBP-1 and SREBP-2 on the sterol regulatory element of the PCSK9 promoter. PCSK9 protein levels decreased by K-312 treatment in the circulating blood of cholesterol-fed rabbits, as determined by two independent mass spectrometry approaches, including the recently developed, highly sensitive parallel reaction monitoring method. New CETP inhibitor K-312 decreases LDL cholesterol and PCSK9 levels, serving as a new therapy for dyslipidemia and cardiovascular disease. Copyright © 2015 the American Physiological Society.

  16. SDF-1 promotes ox-LDL induced vascular smooth muscle cell proliferation.

    PubMed

    Li, Ling-Xing; Zhang, Xian-Feng; Bai, Xue; Tong, Qian

    2013-09-01

    The mechanism of the regulatory roles of stromal cell derived factor-1 (SDF-1)/C-X-C motif receptor 4 (CXCR4) on cell proliferation and apoptosis in vascular smooth muscle cells (VSMCs) via the protein kinase C (PKC) and nuclear factor-kappa B (NF-κB) signalling pathways have been investigated. Rat aortic VSMCs were treated with control or an oxidised low-density lipoprotein (ox-LDL) atherosclerosis (AS) model. Cells exposed to the AS model were treated with SDF-1 plus inhibitors specific for PKC (Ro31-8220), CXCR4 (12G5) or NF-κB (pyrrolidine dithiocarbamate, PDTC). Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and apoptosis by flow cytometry. NF-κB protein expression was analysed using Western blotting. The proliferation rate in the AS model group was significantly higher than the control group, but lower than the SDF-1 group (P < 0.05). Apoptosis in the AS model group (ox-LDL) was significantly higher than the normal control group (P < 0.05). In addition, the apoptosis rate in the SDF-1 group was significantly lower than the normal control group (P < 0.05); however, there was no difference from the Ro31-8220 group. NF-κB protein expression in the SDF-1 group was significantly higher than the AS model (ox-LDL) group (P < 0.05). In conclusion, SDF-1 can promote the proliferation of VSMCs induced by ox-LDL and inhibit cell apoptosis, via the SDF-1/CXCR4 axis.

  17. Oxidized LDL accumulation in experimental renal ischemia reperfusion injury model.

    PubMed

    Kulah, Eyup; Tascilar, Oge; Acikgoz, Serefden; Tekin, Ishak Ozel; Karadeniz, Guldeniz; Can, Murat; Gun, Banu; Barut, Figen; Comert, Mustafa

    2007-01-01

    The aim of this study was to identify oxidative damage of kidney during ischemia reperfusion injury (IRI) by evaluating changes in lipid peroxidation markers in tissue and blood by an experimental model. Oxidized LDL (ox-LDL) was used as an oxidative stress biomarker, whereas paraoxonase (PON-1) activity was used as an antioxidative biomarker. Sixty-three male Wistar rats were randomly assigned into three groups: renal IRI, sham, and control. In the renal IRI group, the right kidney was removed and the artery and vein of the left kidney were clamped for 90 minutes. The presence of ox-LDL in the kidney tissue sections was determined by using an immunofluorescent staining method. The plasma ox-LDL levels did not increase significantly at the 24th hour following IRI, made a peak at the 48th hour, and declined at the 72nd hour. Accumulation of ox-LDL was detected in the kidney tissue on the 24th, 48th, and 72nd hours of the renal IRI. Serum PON-1 levels have peaked on the 24th hour and then declined. This study demonstrates the accumulation of ox-LDL molecules in the renal tissues of the IRI model. Future strategies aimed to reduce the lipid peroxidation during the initial hours of renal IRI may be useful to prevent complications of ischemia.

  18. Oxidized LDL and LOX-1 in Experimental Sepsis

    PubMed Central

    Al-Banna, Nadia; Lehmann, Christian

    2013-01-01

    Oxidized low-density lipoproteins (oxLDL) and the lectin-like oxLDL receptor-1 (LOX-1) are upregulated in inflammation. Because of the importance of inflammation and capillary leakage in the impairment of the microcirculation, which in turn contributes to the development of sepsis and multiorgan failure, the role of oxidized LDL and LOX-1 as players of intestinal inflammation is of great interest. In fact, the blockade of LOX-1 during experimental endotoxemia was effective in reducing leukocyte activation. There are several mechanisms by which oxLDL can participate in local and systemic inflammation, including cell proliferation, apoptosis, capillary perfusion, leukocyte-endothelial cell interactions, and endothelial activation. This review highlights the evidence relating oxLDL and LOX-1 to proinflammatory disease mechanisms. We also indicate situations when oxLDL, because of exposure time, dose, or degree of oxidization, is involved in disease resolution. Modulation of LOX-1 response could be utilized for the treatment of local and systemic inflammation, but the successful use of this target requires further understanding of its broad effects. PMID:24000272

  19. Estradiol protective role in atherogenesis through LDL structure modification

    NASA Astrophysics Data System (ADS)

    Papi, Massimiliano; Brunelli, Roberto; Ciasca, Gabriele; Maiorana, Alessandro; Maulucci, Giuseppe; Palmieri, Valentina; Parasassi, Tiziana; De Spirito, Marco

    2016-07-01

    Relevant physiological functions are exerted by circulating low density lipoprotein (LDL) as well as eventual pathological processes triggering atherogenesis. Modulation of these functions can well be founded on modifications of LDL structure. Given its large dimension, multicomponent organization and strong interactions between the protein apoB-100 and lipids, determining LDL 3D structure remains a challenge. We propose a novel quantitative physical approach to this complex biological problem. We introduce a three-component model, fitted to small angle x-ray scattering data on LDL maintained in physiological conditions, able to achieve a consistent 3D structure. Unexpected features include three distinct protein domains protruding out of a sphere, quite rough in its surface, where several core lipid areas are exposed. All LDL components are affected by 17-β-estradiol (E2) binding to apoB-100. Mostly one of the three protruding protein domains, dramatically reducing its presence on the surface and with a consequent increase of core lipids’ exposure. This result suggests a structural basis for some E2 protecting roles and LDL physiological modifications.

  20. Endothelial Chlamydia pneumoniae infection promotes oxidation of LDL.

    PubMed

    Dittrich, Ralf; Dragonas, Charalampos; Mueller, Andreas; Maltaris, Theodoros; Rupp, Jan; Beckmann, Matthias W; Maass, Matthias

    2004-06-25

    The bacterium Chlamydia pneumoniae chronically infects atheromatous lesions and is linked to atherosclerosis by modifying inflammation, proliferation, and the lipid metabolism of blood monocytes. As continuous LDL modification in the vascular intima is crucial for atherogenesis we investigated the impact of endothelial infection on LDL oxidation. HUVEC were infected with a vascular C. pneumoniae strain. Supernatants of infected cells but not cell lysates increased lipid peroxidation products (6.44 vs 6.14 nmol/ml, p<0.05) as determined by thiobarbituric acid reacting substances assay. Moreover, supernatants rendered human LDL more susceptible to oxidation as shown in a copper-ion catalysed LDL oxidation assay by a 16% reduction of LDL resistance against pro-oxidative stimuli (p<0.05). Chlamydial infection of vascular endothelial cells releases acellular components that convert LDL to its proatherogenic form and reduce its resistance against oxidation. Foci of chronic endothelial chlamydial infection may thus continuously contribute to the dysregulated lipid metabolism that promotes atherogenesis.

  1. Lab-on-a-chip sensor for detection of highly electronegative heavy metals by anodic stripping voltammetry

    PubMed Central

    Jothimuthu, Preetha; Wilson, Robert A.; Herren, Josi; Haynes, Erin N.; Heineman, William R.; Papautsky, Ian

    2013-01-01

    This work describes development of a lab-on-a-chip sensor for electrochemical detection of highly electro-negative heavy metals such as manganese and zinc by anodic stripping voltammetry. The sensor consists of a three-electrode system, with a bismuth working electrode, a Ag/AgCl reference electrode, and a Au auxiliary electrode. Hydrolysis at the auxiliary electrode is a critical challenge in such electrochemical sensors as its onset severely limits the ability to detect electronegative metals. The bismuth working electrode is used due to its comparable negative detection window and reduced toxicity with respect to a conventional mercury electrode. Through optimization of the sensor layout and the working electrode surface, effects of hydrolysis were substantially reduced and the potential window was extended to the −0.3 to −1.9 V range (vs. Ag/AgCl reference electrode), which is far more negative than what is possible with conventional Au, Pt, or carbon electrodes. The described lab-on-a-chip sensor for the first time permits reliable and sensitive detection of the highly electronegative manganese. The favorable performance of the bismuth electrode coupled with its environmentally-friendly nature make the described sensor attractive for applications where disposable chips are desirable. With further development and integrated sample preparation, the lab-on-a-chip may be converted into a point-of-care platform for monitoring heavy metals in blood (e.g., assessment of manganese exposure). PMID:21479538

  2. Lab-on-a-chip sensor for detection of highly electronegative heavy metals by anodic stripping voltammetry.

    PubMed

    Jothimuthu, Preetha; Wilson, Robert A; Herren, Josi; Haynes, Erin N; Heineman, William R; Papautsky, Ian

    2011-08-01

    This work describes development of a lab-on-a-chip sensor for electrochemical detection of highly electronegative heavy metals such as manganese and zinc by anodic stripping voltammetry. The sensor consists of a three-electrode system, with a bismuth working electrode, a Ag/AgCl reference electrode, and a Au auxiliary electrode. Hydrolysis at the auxiliary electrode is a critical challenge in such electrochemical sensors as its onset severely limits the ability to detect electronegative metals. The bismuth working electrode is used due to its comparable negative detection window and reduced toxicity with respect to a conventional mercury electrode. Through optimization of the sensor layout and the working electrode surface, effects of hydrolysis were substantially reduced and the potential window was extended to the -0.3 to -1.9 V range (vs. Ag/AgCl reference electrode), which is far more negative than what is possible with conventional Au, Pt, or carbon electrodes. The described lab-on-a-chip sensor for the first time permits reliable and sensitive detection of the highly electronegative manganese. The favorable performance of the bismuth electrode coupled with its environmentally-friendly nature make the described sensor attractive for applications where disposable chips are desirable. With further development and integrated sample preparation, the lab-on-a-chip may be converted into a point-of-care platform for monitoring heavy metals in blood (e.g., assessment of manganese exposure).

  3. Symmetry laws improve electronegativity equalization by orders of magnitude and call for a paradigm shift in conceptual density functional theory.

    PubMed

    von Szentpály, László

    2015-03-05

    The strict Wigner-Witmer symmetry constraints on chemical bonding are shown to determine the accuracy of electronegativity equalization (ENE) to a high degree. Bonding models employing the electronic chemical potential, μ, as the negative of the ground-state electronegativity, χ(GS), frequently collide with the Wigner-Witmer laws in molecule formation. The violations are presented as the root of the substantially disturbing lack of chemical potential equalization (CPE) in diatomic molecules. For the operational chemical potential, μ(op), the relative deviations from CPE fall between -31% ≤ δμ(op) ≤ +70%. Conceptual density functional theory (cDFT) cannot claim to have operationally (not to mention, rigorously) proven and unified the CPE and ENE principles. The solution to this limitation of cDFT and the symmetry violations is found in substituting μ(op) (i) by Mulliken's valence-state electronegativity, χ(M), for atoms and (ii) its new generalization, the valence-pair-affinity, α(VP), for diatomic molecules. Mulliken's χ(M) is equalized into the α(VP) of the bond, and the accuracy of ENE is orders of magnitude better than that of CPE using μ(op). A paradigm shift replacing the dominance of ground states by emphasizing valence states seems to be in order for conceptual DFT.

  4. Calpain-1 Mediated Disorder of Pyrophosphate Metabolism Contributes to Vascular Calcification Induced by oxLDL

    PubMed Central

    Lu, Meili; Zhang, Xiaowen; Dai, Chunmei; Mei, Meng; Zhang, Suping; Wang, Hongxin; Song, Qing

    2015-01-01

    We previously reported that oxidized low density lipoprotein (oxLDL) accelerated the calcification in aorta of rats and rat vascular smooth muscle cells (RVSMCs). However, the molecular mechanism underlying the acceleration remains poorly understood. The present study aimed to investigate the role of calpain-1, Ca2+-sensitive intracellular cysteine proteases, in the vascular calcification of rats treated with both high dose of vitamin D2 and high cholesterol diet. The results showed that calpain activity significantly increased in calcified aortic tissue of rats and RVSMCs treated with oxLDL. Specific calpain inhibitor I (CAI, 0.5mg/kg, intraperitoneal) inhibited the vascular calcification in rats with hypercholesterolemia accompanied by the increase in the level of extracellular inorganic pyrophosphate (PPi), the endogenous inhibitor of vascular calcification. In addition, CAI increased the content of adenosine triphosphate (ATP), decreased the activity, mRNA and protein expression of alkaline phosphatase (ALP) and reduced the production of superoxide anion in calcified aortic tissue. CAI also increased the activity of ATP synthase as well as protein expression of ATP5D, δ subunit of ATP synthase. In the in vitro study, suppression of calpain-1 using siRNA assay inhibited the calcium deposition, increased the levels of PPi and ATP, improved the activity of ATP synthase as well as protein expression of ATP5D in RVSMCs treated with oxLDL. Calpain-1 suppression also decreased the activity, mRNA and protein expression of ALP and reduced the mitochondrial ROS (Mito-ROS) production in RVSMCs. However, mito-TEMPO, the mitochondria-targeted ROS scavenger, reduced the calcium deposition, increased the PPi in culture medium, decreased the activity, mRNA and protein expression of ALP in RVSMCs treated with oxLDL. Taken together, the results suggested that calpain-1 activation plays critical role in vascular calcification caused by oxLDL, which might be mediated by PPi

  5. [Inhibitory effect of ilexpernoside C from Ilex pernyi on aggregated LDL-induced foam cells formation].

    PubMed

    Lun, Qi-Xing; Liu, Bing-Lin; Li, Jun; Zhao, Yun-Fang; Zheng, Jiao; Tu, Peng-Fei

    2016-02-01

    The aggregation of macrophage-derived foam cells on vascular wall is considered to be a main cause of atherosclerosis. In the present study, we evaluated the inhibitory effect of the compound ilexpernoside C (IC1) extracted from Ilex pernyi (Aquifoliaceae) on foam cell formation in THP-1 macrophages cells which were induced by low density lipoproteins aggregates (LDL aggregates). Results showed that IC1 could significantly inhibit the formation of foam cells. The analysis on related receptors of foam cells indicated that IC1 could significantly decrease the expression of low density lipoprotein-related receptor 1(LRP1). Therefore, these findings indicated that IC1 inhibited the formation of foam cells by inhibiting endocytosis of macrophages, thus it may act as a potential anti-atherosclerotic agent. Copyright© by the Chinese Pharmaceutical Association.

  6. Aggregation of LDL with chondroitin-4-sulfate makes LDL oxidizable in the presence of water-soluble antioxidants.

    PubMed

    Abuja, Peter M

    2002-02-13

    The content of plasma and arterial interstitial fluid in water-soluble antioxidants makes it unlikely for low-density lipoprotein (LDL) to oxidize by the oxidation mechanisms most frequently discussed. By aggregation of LDL in the presence of chondroitin-4-sulfate (C-4-S), but not with chondroitin-6-sulfate or sphingomyelinase, a complex arises which can oxidize in the presence of 20 microM ascorbate and 300 microM urate. This oxidation sensitivity even persists after the gel-filtration of an LDL/C-4-S/Cu(2+) complex, indicating entrapment of Cu(2+) within. This corresponds well to the known ability of C-4-S to bind copper ions and is a potential mechanism by which LDL oxidation in the arterial intima is facilitated after prolonged retention by the extracellular matrix.

  7. Olive Oil Polyphenols Decrease LDL Concentrations and LDL Atherogenicity in Men in a Randomized Controlled Trial123

    PubMed Central

    Hernáez, Álvaro; Remaley, Alan T; Farràs, Marta; Fernández-Castillejo, Sara; Subirana, Isaac; Schröder, Helmut; Fernández-Mampel, Mireia; Muñoz-Aguayo, Daniel; Sampson, Maureen; Solà, Rosa; Farré, Magí; de la Torre, Rafael; López-Sabater, María-Carmen; Nyyssönen, Kristiina; Zunft, Hans-Joachim F; Covas, María-Isabel; Fitó, Montserrat

    2015-01-01

    Background: Olive oil polyphenols have shown protective effects on cardiovascular risk factors. Their consumption decreased oxidative stress biomarkers and improved some features of the lipid profile. However, their effects on LDL concentrations in plasma and LDL atherogenicity have not yet been elucidated. Objective: Our objective was to assess whether the consumption of olive oil polyphenols could decrease LDL concentrations [measured as apolipoprotein B-100 (apo B-100) concentrations and the total number of LDL particles] and atherogenicity (the number of small LDL particles and LDL oxidizability) in humans. Methods: The study was a randomized, cross-over controlled trial in 25 healthy European men, aged 20–59 y, in the context of the EUROLIVE (Effect of Olive Oil Consumption on Oxidative Damage in European Populations) study. Volunteers ingested 25 mL/d raw low-polyphenol-content olive oil (LPCOO; 366 mg/kg) or high-polyphenol-content olive oil (HPCOO; 2.7 mg/kg) for 3 wk. Interventions were preceded by 2-wk washout periods. Effects of olive oil polyphenols on plasma LDL concentrations and atherogenicity were determined in the sample of 25 men. Effects on lipoprotein lipase (LPL) gene expression were assessed in another sample of 18 men from the EUROLIVE study. Results: Plasma apo B-100 concentrations and the number of total and small LDL particles decreased (mean ± SD: by 5.94% ± 16.6%, 11.9% ± 12.0%, and 15.3% ± 35.1%, respectively) from baseline after the HPCOO intervention. These changes differed significantly from those after the LPCOO intervention, which resulted in significant increases of 6.39% ± 16.6%, 4.73% ± 22.0%, and 13.6% ± 36.4% from baseline (P < 0.03). LDL oxidation lag time increased by 5.0% ± 10.3% from baseline after the HPCOO intervention, which was significantly different only relative to preintervention values (P = 0.038). LPL gene expression tended to increase by 26% from baseline after the HPCOO intervention (P = 0.08) and did

  8. Definition of the immunogenic forms of modified human LDL recognized by human autoantibodies and by rabbit hyperimmune antibodies.

    PubMed

    Virella, Gabriel; Thorpe, Suzanne R; Alderson, Nathan L; Derrick, M Brooks; Chassereau, Charlyne; Rhett, J Matthew; Lopes-Virella, Maria F

    2004-10-01

    Humans and laboratory animals recognize human modified LDL as immunogenic. Immune complexes (ICs) isolated from human sera contain malondialdehyde-modified LDL (MDA-LDL) and N (epsilon)(carboxymethyl)lysine-modified LDL (CML-LDL) as well as antibodies reacting with MDA-LDL, copper-oxidized LDL (OxLDL), CML-LDL, and advanced glycosylation end product (AGE)-modified LDL. OxLDL and AGE-LDL antibodies isolated from human sera recognize the same LDL modifications and do not react with modified non-LDL proteins. Rabbit antibodies have different reactivity patterns: MDA-LDL antibodies react strongly with MDA-LDL and MDA-BSA but weakly with OxLDL; OxLDL antibodies react strongly with OxLDL and weakly with MDA-LDL; CML-LDL antibodies react with CML-LDL > CML-BSA > AGE-LDL > OxLDL; AGE-LDL antibodies react strongly with AGE-LDL, react weakly with OxLDL, and do not react with CML-LDL. Thus, human and rabbit antibodies seem to recognize different epitopes. Capture assays carried out with all rabbit antibodies showed binding of apolipoprotein B-rich lipoproteins isolated from ICs, suggesting that laboratory-generated epitopes are expressed by in vivo-modified LDL, although they are not necessarily recognized by the human immune system. Thus, the definition of immunogenic forms of modified LDL eliciting human autoimmune responses requires the isolation and characterization of autoantibodies and modified LDL from human samples, whereas rabbit antibodies can be used to detect in vivo-modified human LDL.

  9. TRPV4 calcium-permeable channel is a novel regulator of oxidized LDL-induced macrophage foam cell formation.

    PubMed

    Goswami, Rishov; Merth, Michael; Sharma, Shweta; Alharbi, Mazen O; Aranda-Espinoza, Helim; Zhu, Xiaoping; Rahaman, Shaik O

    2017-09-01

    Cardiovascular disease is the number one cause of death in United States, and atherosclerosis, a chronic inflammatory arterial disease, is the most dominant underlying pathology. Macrophages are thought to orchestrate atherosclerosis by generating lipid-laden foam cells and by secreting inflammatory mediators. Emerging data support a role for a mechanical factor, e.g., matrix stiffness, in regulation of macrophage function, vascular elasticity, and atherogenesis. However, the identity of the plasma membrane mechanosensor and the mechanisms by which pro-atherogenic signals are transduced/maintained are unknown. We have obtained evidence that TRPV4, an ion channel in the transient receptor potential vanilloid family and a known mechanosensor, is the likely mediator of oxidized low-density lipoprotein (oxLDL)-dependent macrophage foam cell formation, a critical process in atherogenesis. Specifically, we found that: i) genetic ablation of TRPV4 or pharmacologic inhibition of TRPV4 activity by a specific antagonist blocked oxLDL-induced macrophage foam cell formation, and ii) TRPV4 deficiency prevented pathophysiological range matrix stiffness or scratch-induced exacerbation of oxLDL-induced foam cell formation. Mechanistically, we found that: i) plasma membrane localization of TRPV4 was sensitized to the increasing level of matrix stiffness, ii) lack of foam cell formation in TRPV4 null cells was not due to lack of expression of CD36, a major receptor for oxLDL, and iii) TRPV4 channel activity regulated oxLDL uptake but not its binding on macrophages. Altogether, these findings identify a novel role for TRPV4 in regulating macrophage foam cell formation by modulating uptake of oxLDL. These findings suggest that therapeutic targeting of TRPV4 may provide a selective approach to the treatment of atherosclerosis. Copyright © 2017. Published by Elsevier Inc.

  10. Modulation of oxidized-LDL receptor-1 (LOX1) contributes to the antiatherosclerosis effect of oleanolic acid.

    PubMed

    Jiang, Qixiao; Wang, Daoyan; Han, Yantao; Han, Zhiwu; Zhong, Weizhen; Wang, Chunbo

    2015-12-01

    Oleanolic acid (OA) is a bioactive pentacyclic triterpenoid. The current work studied the effects and possible mechanisms of OA in atherosclerosis. Quails (Coturnix coturnix) were treated with high fat diet with or without OA. Atherosclerosis was assessed by examining lipid profile, antioxidant status and histology in serum and aorta. Human umbilical vein endothelial cells (HUVECs) were exposed to 200μg/mL ox-LDL for 24h, then cell viability was assessed with MTT assay; reactive oxygen species (ROS) was assessed with DCFDA staining. Expression levels of LOX-1, NADPH oxidase subunits, nrf2 and ho-1 were measured with real time PCR and western blotting. Furthermore, LOX-1 was silenced with lentivirus and the expression levels assessment was repeated. OA treatment improved the lipid profile and antioxidant status in quails fed with high fat diet. Histology showed decreased atherosclerosis in OA treated animals. Ox-LDL exposure decreased viability and induced ROS generation in HUVECs, and this progression was alleviated by OA pretreatment. Moreover, elevated expression of LOX-1, NADPH oxidase subunits, nrf2 and ho-1 were observed in ox-LDL exposed HUVECs. OA pretreatment prevented ox-LDL induced increase of LOX-1 and NADPH oxidase subunits expression, while further increased nrf2 and ho-1 expression. Silencing of LOX-1 abolished ox-LDL induced effects in cell viability, ROS generation and gene expression. OA could alleviate high fat diet induced atherosclerosis in quail and ox-LDL induced cytotoxicity in HUVECs; the potential mechanism involves modulation of LOX-1 activity, including inhibition of expression of NADPH oxidase subunits and increase of the expression of nrf2 and ho-1. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Metabolism of VLDL and LDL containing apolipoprotein C-III and not other small apolipoproteins – R2

    PubMed Central

    Mendivil, Carlos O; Zheng, Chunyu; Furtado, Jeremy; Lel, Julian; Sacks, Frank M

    2010-01-01

    Objective We aimed to clarify the influence of apolipoprotein C-III (apoCIII) on human apolipoprotein B metabolism. Methods and Results We studied the kinetics of four VLDL, IDL and LDL types containing: (1) OtherApos−CIII−: none of apoCIII, apoAII, apoCI, apoCII or apoE; (2) OtherApos+CIII−: no apoCIII but at least one of the others; (3) OtherApos−CIII+: apoCIII, but not any others; (4) OtherApos+CIII+: apoCIII and at least one other. VLDL and IDL OtherApos−CIII+ and OtherApos−CIII− had similar rates of lipolytic conversion to smaller particles. However, light LDL OtherApos−CIII+ compared to OtherApos−CIII− had much faster conversion to dense LDL, as did light LDL OtherApos+CIII+ compared to OtherApos+CIII−. VLDL and IDL OtherApos−CIII+ had minimal direct removal from circulation, while VLDL and IDL OtherApos+CIII−, rich in apoE, showed fast clearance. Lipoproteins in fraction OtherApos+CIII+ also rich in apoE had very low clearance. Conclusions The results suggest that apoCIII strongly inhibits hepatic uptake of VLDL and IDL overriding the opposite influence of apoE when both are present. The presence of apoCIII on dense VLDL is not associated with slow conversion to IDL, a lipoprotein lipase dependent process; but when on light LDL apoCIII is associated with enhanced conversion to dense LDL, a process involving hepatic lipase. PMID:19910636

  12. The monoterpene terpinolene from the oil of Pinus mugo L. in concert with alpha-tocopherol and beta-carotene effectively prevents oxidation of LDL.

    PubMed

    Grassmann, J; Hippeli, S; Spitzenberger, R; Elstner, E F

    2005-06-01

    Antioxidants from several nutrients, e.g. vitamin E, beta-carotene, or flavonoids, inhibit the oxidative modification of low-density lipoproteins. This protective effect could possibly retard atherogenesis and in consequence avoid coronary heart diseases. Some studies have shown a positive effect of those antioxidants on cardiovascular disease. Another class of naturally occurring antioxidants are terpenoids, which are found in essential oils. The essential oil of Pinus mugo and the contained monoterpene terpinolene effectively prevent low-density lipoprotein (LDL)-oxidation. In order to test the mechanism by which terpinolene protects LDL from oxidation, LDL from human blood plasma enriched in terpinolene was isolated. In this preparation not only the lipid part of LDL is protected against copper-induced oxidation--as proven by following the formation of conjugated dienes, but also the oxidation of the protein part is inhibited, since loss of tryptophan fluorescence is strongly delayed. This inhibition is due to a retarded oxidation of intrinsic carotenoids of LDL, and not, as in the case of some flavonoids, attributable to a protection of intrinsic alpha-tocopherol. These results are in agreement with our previous results, which showed the same effects for a monoterpene from lemon oil, i.e. gamma-terpinene.

  13. Oxidized LDL induces in vitro lymphocyte activation in antiphospholipid syndrome.

    PubMed

    Laczik, Renata; Szodoray, Peter; Veres, Katalin; Lakos, Gabriella; Sipka, Sandor; Szegedi, Gyula; Soltész, Pal

    2010-06-01

    Oxidized low-density lipoprotein (oxLDL) is a key feature of the atheromatosus plaque and plays a critical role in foam cell formation and perpetuation of inflammatory processes. In antiphospholipid syndrome (APS), oxLDL molecules form complexes with beta2GPI and become target antigens for autoantibodies, which are detectable in the sera of these patients. oxLDL takes part in the pathogenesis of APS and in the concomitant accelerated atherosclerosis, yet the exact associated immune mechanisms are not clear in details. The aim of this study was to assess the activation and proliferation response of peripheral blood mononuclear cells (PBMCs) derived from patients with APS in the presence of oxLDL. Thirteen patients with APS and nine healthy individuals were enrolled in the study. Separated PBMCs of these patients were cultured in the presence of immunogenic epitope of oxLDL. Lymphocyte proliferation and cytokine secretion (TNF-alpha, IL-2, IFN-gamma, IL-4, and IL-10) were assessed by ELISA. We found significant PBMC proliferation in APS compared to healthy controls (PI/proliferation index/APS: 1.76 vs. PI control: 0.56; p = 0.032). A significant IL-2 and IFN-gamma secretion were detected upon oxLDL stimulus in patients with APS compared to controls (IL-2 cytokine secretion index (CSI) APS: 278.5, IL-2 CSI controls: 65.1; p = 0.025; IFN-gamma CSI APS: 163.2, IFN-gamma CSI controls: 77.4; p = 0.025). Based on our findings, we assume that oxLDL via Th1-type cytokine production and lymphocyte proliferation may contribute to the perpetuation of immune processes in APS.

  14. Atomic interactions of neonicotinoid agonists with AChBP: Molecular recognition of the distinctive electronegative pharmacophore

    PubMed Central

    Talley, Todd T.; Harel, Michal; Hibbs, Ryan E.; Radić, Zoran; Tomizawa, Motohiro; Casida, John E.; Taylor, Palmer

    2008-01-01

    Acetylcholine-binding proteins (AChBPs) from mollusks are suitable structural and functional surrogates of the nicotinic acetylcholine receptors when combined with transmembrane spans of the nicotinic receptor. These proteins assemble as a pentamer with identical ACh binding sites at the subunit interfaces and show ligand specificities resembling those of the nicotinic receptor for agonists and antagonists. A subset of ligands, termed the neonicotinoids, exhibit specificity for insect nicotinic receptors and selective toxicity as insecticides. AChBPs are of neither mammalian nor insect origin and exhibit a distinctive pattern of selectivity for the neonicotinoid ligands. We define here the binding orientation and determinants of differential molecular recognition for the neonicotinoids and classical nicotinoids by estimates of kinetic and equilibrium binding parameters and crystallographic analysis. Neonicotinoid complex formation is rapid and accompanied by quenching of the AChBP tryptophan fluorescence. Comparisons of the neonicotinoids imidacloprid and thiacloprid in the binding site from Aplysia californica AChBP at 2.48 and 1.94 Å in resolution reveal a single conformation of the bound ligands with four of the five sites occupied in the pentameric crystal structure. The neonicotinoid electronegative pharmacophore is nestled in an inverted direction compared with the nicotinoid cationic functionality at the subunit interfacial binding pocket. Characteristic of several agonists, loop C largely envelops the ligand, positioning aromatic side chains to interact optimally with conjugated and hydrophobic regions of the neonicotinoid. This template defines the association of interacting amino acids and their energetic contributions to the distinctive interactions of neonicotinoids. PMID:18477694

  15. Bicarbonate-dependent, carbonate radical anion-driven tocopherol-mediated human LDL peroxidation: an in vitro and in vivo study.

    PubMed

    Lapenna, Domenico; Ciofani, Giuliano; Cuccurullo, Chiara; Neri, Matteo; Giamberardino, Maria Adele; Cuccurullo, Franco

    2012-11-01

    We have here investigated possible occurrence of bicarbonate-dependent, carbonate radical anion (CO(3)(•-))-driven tocopherol-mediated human LDL peroxidation (TMP) in vitro and in vivo. CO(3)(•-), generated in vitro by the SOD1/H(2)O(2)/bicarbonate system, readily promoted TMP, which was dependent on α-tocopherol and bicarbonate concentrations, and was inhibited by the CO(3)(•-) scavenger ethanol; moreover, TMP induced in vitro by the SOD1/H(2)O(2)/bicarbonate system occurred in the presence of α-tocopherol that typically underwent slow oxidative consumption. In the in vivo clinical setting, we showed that, compared to controls, hypertensive patients with diuretic-induced metabolic alkalosis and heightened blood bicarbonate concentration had lipid hydroperoxide burden and decreased α-tocopherol content in the LDL fraction, with direct significant correlation between the LDL levels of α-tocopherol and those of lipid hydroperoxides; remarkably, after resolution of metabolic alkalosis, together with normalization of blood bicarbonate concentration, the LDL content of lipid hydroperoxides was decreased and that of α-tocopherol augmented significantly. These findings suggest bicarbonate-dependent, CO(3)(•-)-driven LDL TMP in vivo. In conclusion, the present study highlights the occurrence of bicarbonate-dependent, CO(3)(•-)-driven human LDL TMP, the role of which in pathological conditions such as atherosclerosis warrants, however, further investigation.

  16. [Lowering LDL-cholesterol: the lower the better?

    PubMed

    Bots, M L

    2017-01-01

    There is still a debate about the optimal LDL level to achieve with pharmacological treatment. Some support the 'the lower, the better' approach, others support 'a level less than 2.5 mmol/l suffices'. Two recent JAMA papers lend support to both views. So what to believe? The issue is whether those with an achieved low LDL level (< 1.8 mmol/l) carry a lower vascular risk than those with an LDL between 1.8 and 2.5 mmol/l. To study this, both groups need to be identical with respect to all other factors that determine the risk, and therefore only differ in their respective LDL levels. So it is all about adjustment for confounding. One paper (shows no benefit for a LDL level lower than 2.5 mmol/l) is based on individual participant information, allowing for optimal adjustment. The other paper (shows the lower, the better) is based on mean levels of trial groups, and cannot adequately adjust for confounding. These examples demonstrate that study design is very important.

  17. Higher circulating levels of OxLDL % of LDL are associated with subclinical atherosclerosis in female patients with systemic lupus erythematosus.

    PubMed

    Ahmad, Hamada Mohammad; Sarhan, Esmat M; Komber, Usama

    2014-05-01

    Because systemic lupus erythematosus (SLE) is associated with a high risk of atherosclerosis, a process that involves low-density lipoprotein (LDL) oxidation, we examined the hypothesis that raised fraction of LDL that is converted to oxidized (Ox) LDL expressed in OxLDL % of LDL (OxLDL %) is associated with the subclinical atherosclerosis in SLE. A cohort of 60 SLE patients with no previous history of cardiovascular disease had carotid artery ultrasound to identify plaques and to measure intima-media thickness (IMT). Forty females with rheumatoid arthritis (RA) were also enrolled in the study to serve as a control group. Plasma OxLDL concentrations were measured, and the OxLDL % of LDL were calculated. Traditional and SLE-related risk factors for atherosclerosis were evaluated. OxLDL % were significantly higher in SLE patients compared to patients with RA (p = 0.0311). OxLDL % were significantly higher in SLE patients with plaques than in those without plaques (p < 0.001). SLE patients in the highest IMT quartile have higher OxLDL % than patients in the lower three quartiles (p < 0.001). The odd ratio (OR) for the OxLDL % in patients with plaques was 6.143 (p < 0.001) when compared to patient without plaques, while OR for the OxLDL % was 8.34 (p < 0.001) in the patients with highest IMT quartile as compared to patients in the lower three quartiles after adjustment for confounding factors in logistic regression analysis. Our data provide evidence of an association between the circulating levels of OxLDL % of LDL with the risk for developing atherosclerosis in patients with SLE.

  18. Mitotic Spindle Defects and Chromosome Mis-Segregation Induced by LDL/Cholesterol—Implications for Niemann-Pick C1, Alzheimer’s Disease, and Atherosclerosis

    PubMed Central

    Granic, Antoneta; Potter, Huntington

    2013-01-01

    Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol

  19. Macrophage-specific overexpression of interleukin-5 attenuates atherosclerosis in LDL receptor-deficient mice.

    PubMed

    Zhao, W; Lei, T; Li, H; Sun, D; Mo, X; Wang, Z; Zhang, K; Ou, H

    2015-08-01

    Interleukin-5 (IL-5) increases the secretion of natural T15/EO6 IgM antibodies that inhibit the uptake of oxidized low-density lipoprotein (LDL) by macrophages. This study aimed to determine whether macrophage-specific expression of IL-5 in LDL receptor-deficient mice (Ldlr(-/-)) could improve cholesterol metabolism and reduce atherosclerosis. To induce macrophage-specific IL-5 expression, the pLVCD68-IL5 lentivirus was delivered into Ldlr(-/-) mice via bone marrow transplantation. The recipient mice were fed a Western-type diet for 12 weeks to induce lesion formation. We found that IL-5 was efficiently and specifically overexpressed in macrophages in recipients of pLVCD68-IL5-transduced bone marrow cells (BMC). Plasma titers of T15/EO6 IgM antibodies were significantly elevated by 58% compared with control mice transplanted with pLVCD68 lacking the IL-5 coding sequence. Plaque areas of aortas in IL-5-overexpressing mice were reduced by 43% and associated with a 2.4-fold decrease in lesion size at the aortic roots when compared with mice receiving pLVCD68-transduced BMCs. The study showed that macrophage-specific overexpression of IL-5 inhibited the progression of atherosclerotic lesions. These findings suggest that modulation of IL-5 cytokine expression represents a potential strategy for intervention of familial hypercholesterolemia and other cardiovascular diseases.

  20. A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression.

    PubMed

    Singh, Amar Bahadur; Kan, Chin Fung Kelvin; Shende, Vikram; Dong, Bin; Liu, Jingwen

    2014-07-01

    It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3'UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation.

  1. Exogenous L-arginine and HDL can alter LDL and ox-LDL-mediated platelet activation: using platelet P-selectin receptor numbers.

    PubMed

    Sener, Azize; Enc, Elif; Ozsavci, Derya; Vanizor-Kural, Birgul; Yanikkaya-Demirel, Gulderen; Oba, Rabia; Uras, Fikriye; Demir, Muzaffer

    2011-01-01

    The aim of this study is to investigate the effects of exogenous L-arginine and HDL on LDL and oxidized LDL (ox-LDL)-mediated platelet activation. Adenosine diphosphate (ADP)-activated platelets have been incubated with lipoproteins with or without L-arginine. P-selectin receptor numbers per platelet have been measured by flow cytometry. After incubation with only L-arginine (without lipoproteins), platelet nitric oxide (NO) levels and P-selectin receptor numbers significantly increased compared to the controls (P < .05). After incubation with LDL or ox-LDL, receptor numbers of P-selectin significantly increased (P < .001). However, P-selectin receptor numbers in platelets treated with L-arginine + LDL or L-arginine + ox-LDL decreased compared to the levels in platelets treated with only LDL or ox-LDL (P < .01, P < .001, respectively). Addition of HDL to L-arginine + ox-LDL caused significant reduction in P-selectin receptor numbers as in the control values (P < .001).We have concluded that L-arginine causes enhanced platelet NO levels and blocks the effects of LDL or ox-LDL on platelet P-selectin receptor numbers and HDL also strengthens this effect of L-arginine.

  2. OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD35

    USDA-ARS?s Scientific Manuscript database

    OxLDL binding to CD36 is shown to result in macrophage activation and foam cell formation that have been implicated in atherosclerosis. However, CD36 has also been shown to induce inflammatory response to other ligands besides oxLDL. During the course of blocking CD36 oxLDL binding function using an...

  3. Boron tracedrug design for neutron dynamic therapeutics for LDL.

    PubMed

    Hori, Hitoshi; Nazumi, Yoshijiro; Uto, Yoshihiro

    2013-01-01

    We describe our solution for removal of the low-density lipoprotein (LDL) depot contained in proteins and lipids as a 'druggable' target for atherosclerotic cardiovascular diseases by neutron dynamic therapy (NDT), which we developed using boron tracedrugs for NDT against bovine serum albumin as a model protein. Thus, we examined, among our developed boron tracedrugs, a boron-containing curcuminoid derivative UTX-51, to destroy freshly isolated human LDL dynamically under irradiated thermal neutron to obtain a decreased intensity of band of LDL treated with UTX-51 and thermal neutron irradiation in their SDS-PAGE and electrophoresis analysis. These results suggest that UTX-51 might be a novel candidate of 'beyond chemical' therapeutic agents for atherosclerotic cardiovascular disease.

  4. Lectin-like oxidized LDL receptor-1 expresses in mouse bone marrow-derived mesenchymal stem cells and stimulates their proliferation

    SciTech Connect

    Zhang, Fenxi; Wang, Congrui; Jing, Suhua; Ren, Tongming; Li, Yonghai; Cao, Yulin; Lin, Juntang

    2013-04-15

    The bone marrow-derived mesenchymal stem cells (bmMSCs) have been widely used in cell transplant therapy, and the proliferative ability of bmMSCs is one of the determinants of the therapy efficiency. Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) as a transmembrane protein is responsible for binding, internalizing and degrading oxidized low density lipoprotein (ox-LDL). It has been identified that LOX-1 is expressed in endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts and monocytes. In these cells, low concentration of ox-LDL (<40 μg/mL) stimulates their proliferation via LOX-1 activation. However, it is poor understood that whether LOX-1 is expressed in bmMSCs and which role it plays. In this study, we investigated the status of LOX-1 expression in bmMSCs and its function on bmMSC proliferation. Our results showed that primary bmMSCs exhibiting a typical fibroblast-like morphology are positive for CD44 and CD90, but negative for CD34 and CD45. LOX-1 in both mRNA and protein levels is highly expressed in bmMSCs. Meanwhile, bmMSCs exhibit a strong potential to take up ox-LDL. Moreover, LOX-1 expression in bmMSCs is upregulated by ox-LDL with a dose- and time-dependent manner. Presence of ox-LDL also enhances the proliferation of bmMSCs. Knockdown of LOX-1 expression significantly inhibits ox-LDL-induced bmMSC proliferation. These findings indicate that LOX-1 plays a role in bmMSC proliferation. - Highlights: ► LOX-1 expresses in bmMSCs and mediates uptake of ox-LDL. ► Ox-LDL stimulates upregulation of LOX-1 in bmMSCs. ► Ox-LDL promotes bmMSC proliferation and expression of Mdm2, phosphor-Akt, phosphor-ERK1/2 and phosphor-NF-κB. ► LOX-1 siRNA inhibits ox-LDL-induced bmMSC proliferation and expression cell survival signals.

  5. Oxidized LDL-bound CD36 recruits an Na⁺/K⁺-ATPase-Lyn complex in macrophages that promotes atherosclerosis.

    PubMed

    Chen, Yiliang; Kennedy, David J; Ramakrishnan, Devi Prasadh; Yang, Moua; Huang, Wenxin; Li, Zhichuan; Xie, Zijian; Chadwick, Alexandra C; Sahoo, Daisy; Silverstein, Roy L

    2015-09-08

    One characteristic of atherosclerosis is the accumulation of lipid-laden macrophage foam cells in the arterial wall. We have previously shown that the binding of oxidized low-density lipoprotein (oxLDL) to the scavenger receptor CD36 activates the kinase Lyn, initiating a cascade that inhibits macrophage migration and is necessary for foam cell generation. We identified the plasma membrane ion transporter Na(+)/K(+)-ATPase as a key component in the macrophage oxLDL-CD36 signaling axis. Using peritoneal macrophages isolated from Atp1a1 heterozygous or Cd36-null mice, we demonstrated that CD36 recruited an Na(+)/K(+)-ATPase-Lyn complex for Lyn activation in response to oxLDL. Macrophages deficient in the α1 Na(+)/K(+)-ATPase catalytic subunit did not respond to activation of CD36, showing attenuated oxLDL uptake and foam cell formation, and oxLDL failed to inhibit migration of these macrophages. Furthermore, Apoe-null mice, which are a model of atherosclerosis, were protected from diet-induced atherosclerosis by global deletion of a single allele encoding the α1 Na(+)/K(+)-ATPase subunit or reconstitution with macrophages that lacked an allele encoding the α1 Na(+)/K(+)-ATPase subunit. These findings identify Na(+)/K(+)-ATPase as a potential target for preventing or treating atherosclerosis. Copyright © 2015, American Association for the Advancement of Science.

  6. The ERK1/2 pathway participates in the upregulation of the expression of mesenteric artery α1 receptors by intravenous tail injections of mmLDL in mice.

    PubMed

    Wang, Jun-Jie; Chen, Xiao-Lan; Xu, Cang-Bao; Jiang, Gao-Feng; Lin, Jie; Liu, En-Qi; Qin, Xu-Ping; Li, Jie

    2016-02-01

    Minimally modified low density lipoprotein (mmLDL) is a risk factor for cardiovascular diseases. However, no studies examining the effect of mmLDL on vascular smooth muscle receptors have been released. The current study investigated the effect of mmLDL on the mesenteric artery α1 adrenoceptor and the molecular mechanisms. Mice were divided into the normal saline (NS), mmLDL, and mmLDL+U0126 groups. In the mmLDL+U0126 group, the animals were subjected to an intravenous tail injection of mmLDL and an intraperitoneal injection of U0126. Vascular tension caused by noradrenaline (NA) in mesenteric arteries was measured with a sensitive myograph system. The serum levels of oxLDL, TNF-α, and IL-1β were detected using enzyme-linked immunosorbent assays. The expressions of the α1 adrenoceptor, the α2 adrenoceptor, TNF-α, IL-1β, and pERK1/2 were detected using real-time polymerase chain reactions and Western blot analysis. Compared with the NS group, the mmLDL group exhibited a noticeably enhanced NA shrinkage dose-response curve and a significantly increased Emax value (P<0.01). Prazosin (α1 adrenoceptor antagonist) caused a noticeable right shift of the dose-response curve. U0126 inhibited the increases in the serum levels and vessel wall expression of IL-1β and TNF-α and enhanced the NA shrinkage dose-response curve caused by mmLDL, as observed by a significantly decreased Emax value (P<0.01). It inhibited the increased α1 adrenoceptor expression caused by mmLDL. The serum levels of IL-1β and TNF-α demonstrated a positive correlation with the NA-induced maximum shrinkage percentage. U0126 inhibited the mmLDL-induced increase in the pERK1/2 protein level in the vessel wall. In conclusion, mmLDL increased the serum levels of IL-1β and TNF-α in vivo by activating the ERK1/2 pathway, which resulted in α1 receptor-mediated vasoconstriction and an increase in the expression of α1 adrenoceptor. The results of this study may provide new ideas for the prevention

  7. Numerical simulations used for a validity check on the laser induced photo-detachment diagnostic method in electronegative plasmas

    SciTech Connect

    Oudini, N.; Taccogna, F.; Aanesland, A.

    2014-06-15

    Laser photo-detachment is used as a method to measure or determine the negative ion density and temperature in electronegative plasmas. In essence, the method consists of producing an electropositive channel (negative ion free region) via pulsed laser photo-detachment within an electronegative plasma bulk. Electrostatic probes placed in this channel measure the change in the electron density. A second pulse might be used to track the negative ion recovery. From this, the negative ion density and temperature can be determined. We study the formation and relaxation of the electropositive channel via a two-dimensional Particle-In-Cell/Mote Carlo collision model. The simulation is mainly carried out in a Hydrogen plasma with an electronegativity of α = 1, with a parametric study for α up to 20. The temporal and spatial evolution of the plasma potential and the electron densities shows the formation of a double layer (DL) confining the photo-detached electrons within the electropositive channel. This DL evolves into two fronts that move in the opposite directions inside and outside of the laser spot region. As a consequence, within the laser spot region, the background and photo-detached electron energy distribution function relaxes/thermalizes via collisionless effects such as Fermi acceleration and Landau damping. Moreover, the simulations show that collisional effects and the DL electric field strength might play a non-negligible role in the negative ion recovery within the laser spot region, leading to a two-temperature negative ion distribution. The latter result might have important effects in the determination of the negative ion density and temperature from laser photo detachment diagnostic.

  8. Charge-Shift Corrected Electronegativities and the Effect of Bond Polarity and Substituents on Covalent-Ionic Resonance Energy.

    PubMed

    James, Andrew M; Laconsay, Croix J; Galbraith, John Morrison

    2017-07-13

    Bond dissociation energies and resonance energies for HnA-BHm molecules (A, B = H, C, N, O, F, Cl, Li, and Na) have been determined in order to re-evaluate the concept of electronegativity in the context of modern valence bond theory. Following Pauling's original scheme and using the rigorous definition of the covalent-ionic resonance energy provided by the breathing orbital valence bond method, we have derived a charge-shift corrected electronegativity scale for H, C, N, O, F, Cl, Li, and Na. Atomic charge shift character is defined using a similar approach resulting in values of 0.42, 1.06, 1.43, 1.62, 1.64, 1.44, 0.46, and 0.34 for H, C, N, O, F, Cl, Li, and Na, respectively. The charge-shift corrected electronegativity values presented herein follow the same general trends as Pauling's original values with the exception of Li having a smaller value than Na (1.57 and 1.91 for Li and Na respectively). The resonance energy is then broken down into components derived from the atomic charge shift character and polarization effects. It is then shown that most of the resonance energy in the charge-shift bonds H-F, H3C-F, and Li-CH3 and borderline charge-shift H-OH is associated with polarity rather than the intrinsic atomic charge-shift character of the bonding species. This suggests a rebranding of these bonds as "polar charge-shift" rather than simply "charge-shift". Lastly, using a similar breakdown method, it is shown that the small effect the substituents -CH3, -NH2, -OH, and -F have on the resonance energy (<10%) is mostly due to changes in the charge-shift character of the bonding atom.

  9. Modeling the magnetic properties of lanthanide complexes: relationship of the REC parameters with Pauling electronegativity and coordination number.

    PubMed

    Baldoví, José J; Gaita-Ariño, Alejandro; Coronado, Eugenio

    2015-07-28

    In a previous study, we introduced the Radial Effective Charge (REC) model to study the magnetic properties of lanthanide single ion magnets. Now, we perform an empirical determination of the effective charges (Zi) and radial displacements (Dr) of this model using spectroscopic data. This systematic study allows us to relate Dr and Zi with chemical factors such as the coordination number and the electronegativities of the metal and the donor atoms. This strategy is being used to drastically reduce the number of free parameters in the modeling of the magnetic and spectroscopic properties of f-element complexes.

  10. Oxidation-induced loss of the ability of HDL to counteract the inhibitory effect of oxidized LDL on vasorelaxation.

    PubMed

    Perségol, Laurence; Brindisi, Marie-Claude; Rageot, David; Pais de Barros, Jean-Paul; Monier, Serge; Vergès, Bruno; Duvillard, Laurence

    2015-11-01

    Several current diseases are associated with an increase in the oxidation of HDL, which is likely to impair their functionality. Our aim was to identify whether oxidation could change the protective effect of HDL against the deleterious effect on vasoreactivity induced by oxidative stress. HDL from healthy subjects were oxidized in vitro by Cu(2+), and the ability of oxidized HDL to counteract the inhibitory effect of oxidized LDL on acetylcholine-induced vasodilation was tested on isolated rabbit aorta rings. Oxidation of HDL was evidenced by the increase in the 7-oxysterols/cholesterol ratio (3.20 ± 1.12 vs 0.02 ± 0.01 % in native HDL, p < 0.05). Oxidized LDL inhibited endothelium-dependent vasodilation (E max = 50.2 ± 5.0 vs 92.5 ± 1.7 % for incubation in Kreb's buffer, p < 0.05) and native HDL counteracted this inhibition (E max = 72.4 ± 4.8 vs 50.2 ± 5.0 % p < 0.05). At the opposite, oxidized HDL had no effect on oxidized LDL-induced inhibition on endothelium-dependent vasorelaxation (E max = 53.7 ± 4.8 vs 50.2 ± 5.0 %, NS). HDL oxidation is associated with a decreased ability of HDL to remove 7-oxysterols from oxidized LDL. In conclusion, these results show that oxidation of HDL induces the loss of their protective effect against endothelial dysfunction, which could promote atherosclerosis in diseases associated with increased oxidative stress.

  11. Inhibition of human low-density lipoprotein oxidation in vitro by ginger extracts.

    PubMed

    Gunathilake, K D Prasanna P; Rupasinghe, H P Vasantha

    2014-04-01

    Oxidative modification of low-density lipoprotein (LDL) is thought to play a key role in atherosclerotic plaque formation. Currently, there is a renewed interest in ginger because of its antioxidants and cardioprotective properties. The effects of ethanol, methanol, ethyl acetate, and hexane solvent extracts of ginger and pure major ginger constituents on Cu(2+)-induced oxidation of human LDL in vitro were examined. The LDL oxidation inhibition by ethanol, methanol, ethyl acetate, and hexane extracts of ginger was 71%, 76%, 67%, and 67%, respectively, at their optimum extraction conditions. Inhibition of LDL oxidation by water extracts of ginger, which was prepared by ultrasonic-assisted extraction conditions of 52°C for 15 min, was about 43%. Phenolic bioactives of ginger-6-gingerols, 8-gingerols, 10-gingerols, and 6-shogaol-seem to be strong inhibitors of Cu(+2)-induced LDL oxidation. Overall, ginger extracts, including the water extract possess the antioxidant activities to inhibit human LDL oxidation in vitro.

  12. In vitro evidence for the protective role of Sida rhomboidea. Roxb extract against LDL oxidation and oxidized LDL-induced apoptosis in human monocyte-derived macrophages.

    PubMed

    Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Devkar, Ranjisinh V; Ramachandran, A V

    2011-06-01

    The present study was undertaken to evaluate protective role of S. rhomboidea. Roxb (SR) leaf extract against in vitro low-density lipoprotein (LDL) oxidation and oxidized LDL (Ox-LDL) induced macrophage apoptosis. Copper and cell-mediated LDL oxidation, Ox-LDL-induced peroxyl radical generation, mitochondrial activity, and apoptosis in human monocyte-derived macrophages (HMDMs) were assessed in presence of SR extract. Results clearly indicated that SR was capable of reducing LDL oxidation and formation of intermediary oxidation products. Also, SR successfully attenuated peroxyl radical formation, mitochondrial dysfunction, nuclear condensation, and apoptosis in Ox-LDL-exposed HMDMs. This scientific report is the first detailed investigation that establishes anti-atherosclerotic potential of SR extract.

  13. Hydrogen sulfide suppresses oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 generation from macrophages via the nuclear factor κB (NF-κB) pathway.

    PubMed

    Du, Junbao; Huang, Yaqian; Yan, Hui; Zhang, Qiaoli; Zhao, Manman; Zhu, Mingzhu; Liu, Jia; Chen, Stella X; Bu, Dingfang; Tang, Chaoshu; Jin, Hongfang

    2014-04-04

    This study was designed to examine the role of hydrogen sulfide (H2S) in the generation of oxidized low-density lipoprotein (ox-LDL)-stimulated monocyte chemoattractant protein 1 (MCP-1) from macrophages and possible mechanisms. THP-1 cells and RAW macrophages were pretreated with sodium hydrosulfide (NaHS) and hexyl acrylate and then treated with ox-LDL. The results showed that ox-LDL treatment down-regulated the H2S/cystathionine-β-synthase pathway, with increased MCP-1 protein and mRNA expression in both THP-1 cells and RAW macrophages. Hexyl acrylate promoted ox-LDL-induced inflammation, whereas the H2S donor NaHS inhibited it. NaHS markedly suppressed NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter in ox-LDL-treated macrophages. Furthermore, NaHS decreased the ratio of free thiol groups in p65, whereas the thiol reductant DTT reversed the inhibiting effect of H2S on the p65 DNA binding activity. Most importantly, site-specific mutation of cysteine 38 to serine in p65 abolished the effect of H2S on the sulfhydration of NF-κB and ox-LDL-induced NF-κB activation. These results suggested that endogenous H2S inhibited ox-LDL-induced macrophage inflammation by suppressing NF-κB p65 phosphorylation, nuclear translocation, DNA binding activity, and recruitment to the MCP-1 promoter. The sulfhydration of free thiol group on cysteine 38 in p65 served as a molecular mechanism by which H2S inhibited NF-κB pathway activation in ox-LDL-induced macrophage inflammation.

  14. LDL in patients with subclinical hypothyroidism shows increased lipid peroxidation.

    PubMed

    Zha, Kexi; Zuo, Changting; Wang, Aihong; Zhang, Bingchang; Zhang, Yan; Wang, Bei; Wang, Yunjia; Zhao, Jiajun; Gao, Ling; Xu, Chao

    2015-08-25

    Population-based studies have demonstrated that subclinical hypothyroidism (SCH) is an independent risk factor for atherosclerosis (OR = 1.9). However, this connection cannot be entirely explained by dyslipidemia accompanied by SCH. Lipid peroxidation also plays an important role in the development of atherosclerosis. In this study, we aimed to evaluate oxidative stress in SCH patients, as measured according to concentrations of hydroxy-octadecadienoic acids (HODEs) and hydroxy-eicosatetraenoic acids (HETEs) in both plasma and low density lipoproteins (LDL). The concentrations of HODEs and HETEs in both LDL and plasma were examined in euthyroid (n = 10), mild SCH (4.5 ≤ TSH < 10 mU/L, n = 10), and significant SCH (TSH ≥ 10 mU/L, n = 10) subjects, using a liquid chromatograph-electrospray ionization- mass spectrometer. Then, we explored the relationship among LDL oxidation, TSH levels, and carotid intima-media thickness (IMT), a biomarker of subclinical atherosclerosis. Serum LDL-C levels and mean-IMT in the significant SCH group were higher than in the euthyroid group (p < 0.05). The HODE and HETE concentrations clearly increased in the significant SCH patients compared with the euthyroid subjects, but there was no difference between the mild SCH and euthyroid groups. Among all subjects, linear and significant positive correlations were identified between TSH and mean-IMT after adjustment for confounding factors (r = 0.480, p = 0.018). Both 9-HODE (r = 0.376, p = 0.041) and 13-HODE (r = 0.447, p = 0.013) in LDL were linearly and positively correlated with TSH. The concentrations of HODEs (both 9-HODE and 13-HODE) in LDL were much higher in the thickened IMT group than in the normal IMT group (p =  .017 and 0.015, respectively). HODEs in LDL were also positively associated with mean-IMT. Our findings showed that lipid peroxidation was higher in the significant SCH patients than in the euthyroid subjects, which suggested that qualitative as well as quantitative

  15. Cryptotanshinone attenuates in vitro oxLDL-induced pre-lesional atherosclerotic events.

    PubMed

    Ang, Kok-Pian; Tan, Heng-Kean; Selvaraja, Malarvilli; Kadir, Arifah A; Somchit, Muhammad N; Akim, Abdah M; Zakaria, Zainul A; Ahmad, Zuraini

    2011-11-01

    Development of early stage atherosclerosis involves the activation of endothelial cells by oxidized low-density lipoprotein (oxLDL) with subsequent increases in endothelial permeability and expression of adhesion molecules favoring the adherence of monocytes to the endothelium. Cryptotanshinone (CTS), a major compound derived from the Chinese herb Salvia miltiorrhiza, is known for its protective effects against cardiovascular diseases. The aim of this study was to determine whether CTS could prevent the oxLDL-induced early atherosclerotic events. OxLDL (100 µg/mL) was used to increase endothelial permeability and induce monocyte-endothelial cell adhesion in human umbilical vein endothelial cells (HUVECs). Endothelial nitric oxide (NO) concentrations, a permeability-regulating molecule, and expressions of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were measured. Results show that a) endothelial hyperpermeability was suppressed by 94 % (p < 0.005), b) monocyte adhesion by 105 % (p < 0.01), and c) ICAM-1 and VCAM-1 expressions by 90 % (p < 0.01) and 150 % (p < 0.005), respectively, when CTS was applied. In contrast, CTS increased NO levels by 129 % (p < 0.01) and was found to be noncytotoxic in the concentrations between 1-10 µM. These findings indicate that CTS suppresses an increase in endothelial permeability, likely due to the restoration of NO bioavailability in endothelial cells. They also indicate that CTS may attenuate monocyte adhesion to endothelial cells through the inhibition of adhesion molecules' expression. Thus, CTS may play an important role in the prevention of early or pre-lesional stage of atherosclerosis. © Georg Thieme Verlag KG Stuttgart · New York.

  16. Lectin-like Oxidized Low-Density Lipoprotein (LDL) Receptor (LOX-1): A Chameleon Receptor for Oxidized LDL.

    PubMed

    Zeya, Bushra; Arjuman, Albina; Chandra, Nimai Chand

    2016-08-16

    LOX-1, one of the main receptors for oxLDL, is found mainly on the surface of endothelial cells. It is a multifacet 52 kDa type II transmembrane protein that structurally belongs to the C-type lectin family. It exists with short intracellular N-terminal and long extracellular C-terminal hydrophilic domains separated by a hydrophobic domain of 26 amino acids. LOX-1 acts like a bifunctional receptor either showing pro-atherogenicity by activating the NFκB-mediated down signaling cascade for gene activation of pro-inflammatory molecules or playing an atheroprotective agent by receptor-mediated uptake of oxLDL in the presence of an anti-inflammatory molecule like IL-10. Mildly, moderately, and highly oxidized LDL show their characteristic features upon LOX-1 activation and its ligand binding indenture. The polymorphic LOX-1 genes are intensively associated with increased susceptibility to myocardial diseases. The splicing variant LOX IN dimerizes with the native form of LOX-1 and protects cells from damage by oxidized LDL. In the developing field of regenerating medicine, LOX-1 is a potential target for therapeutic intervention.

  17. Cellular cholesterol efflux and cholesterol loading capacity of serum: effects of LDL-apheresis[S

    PubMed Central

    Adorni, M. P.; Zimetti, F.; Puntoni, M.; Bigazzi, F.; Sbrana, F.; Minichilli, F.; Bernini, F.; Ronda, N.; Favari, E.; Sampietro, T.

    2012-01-01

    High LDL-cholesterol (LDL-C) characterizes familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH). LDL-apheresis, used in these patients to reduce LDL-C levels, has been shown to also affect HDL levels and composition. We studied LDL-apheresis effects on six FH and nine FCH subjects’ serum capacity to modulate cellular cholesterol efflux, an index of HDL functionality, and to load macrophages with cholesterol. Serum cholesterol efflux capacity (CEC) and macrophage cholesterol loading capacity (CLC) were measured before, immediately after, and two days after LDL-apheresis. The procedure reduced total cholesterol (TC), LDL-C, and apoB plasma levels (−69%, −80% and −74%, respectively), parameters only partially restored two days later. HDL-C and apoA-I plasma levels, reduced after LDL-apheresis (−27% and −16%, respectively), were restored to almost normal levels two days later. LDL-apheresis reduced serum aqueous diffusion (AD) CEC, SR-BI-CEC, and ABCA1-CEC. AD and SR-BI were fully restored whereas ABCA1-CEC remained low two days later. Sera immediately and two days after LDL-apheresis had a lower CLC than pre-LDL-apheresis sera. In conclusion, LDL-apheresis transiently reduces HDL-C levels and serum CEC, but it also reduces also serum capacity to deliver cholesterol to macrophages. Despite a potentially negative effect on HDL levels and composition, LDL-apheresis may counteract foam cells formation. PMID:22414482

  18. Disease Activity, Oxidized-LDL Fraction and Anti-Oxidized LDL Antibodies Influence Cardiovascular Risk in Rheumatoid Arthritis.

    PubMed

    Nowak, Beata; Madej, Marta; Łuczak, Anna; Małecki, Rafał; Wiland, Piotr

    2016-01-01

    Patients with rheumatoid arthritis (RA) have a shortened lifespan compared to the general population. The high rate of premature mortality in the RA population can be attributed to cardiovascular disease (CVD). The aim of the study was to look for non-classic risk factors that can at least partially explain the enhanced cardiovascular (CV) risk in patients with RA. This was an observational study with 37 RA patients and 24 healthy volunteers as controls. The participants' medical history was taken, and systematic coronary risk evaluation (SCORE) and carotid ultrasonography examinations were performed on all the participants. Laboratory tests included antibodies anti-cyclic citrullinated peptide (anti-CCP), inflammatory markers, lipid level, oxidized low-density lipoprotein (oxLDL) level and the level of anti-oxLDL antibodies. Both SCORE and oxLDL fraction were elevated in RA patients as compared to the healthy controls (3.1 ± 3.7 vs. 0.8 ± 1.2, p = 0.005; and 0.029 ± 0.033% vs. 0.014 ± 0.006%, p = 0.04, respectively). In the RA group, the presence of anti-CCP was associated with thickening of the carotid intima-media complex and SCORE elevation. In the RA group, significant correlations were found between SCORE and mean carotid intima-media thickness (IMT; RP = 0.34, p = 0.040), disease activity score (RP = 0.42, p = 0.011), erythrocyte sedimentation rate (ESR; RP = 0.35, p = 0.036), and disease duration (RP = 0.52, p = 0.002). In RA patients with carotid plaques, the oxLDL fraction was significantly elevated in comparison to those without plaques (0.055 ± 0.070% vs. 0.022 ± 0.018%, p = 0.033). In the RA group, there was a significant negative correlation between mean carotid IMT and the serum concentration of anti-oxLDL antibodies (RP = -0.38, p = 0.02). No association was noted between the presence of rheumatoid nodules and SCORE or carotid IMT. Among RA patients, disease activity, ESR, disease duration, the presence of anti-CCP antibodies, the oxLDL

  19. Baicalein is an available anti-atherosclerotic compound through modulation of nitric oxide-related mechanism under oxLDL exposure

    PubMed Central

    Chan, Shih-Hung; Hung, Ching-Hsia; Shih, Jhih-Yuan; Chu, Pei-Ming; Cheng, Yung-Hsin; Tsai, Yi-Ju; Lin, Huei-Chen; Tsai, Kun-Ling

    2016-01-01

    OxLDL facilitate reactive oxygen species (ROS) formation and up-regulation of the executioner caspase-3 via the mitochondrial apoptotic pathway involves several critical steps in human endothelial cells. Previous studies reported that oxLDL-facilitated endothelial oxidative stress is associated with impairment of eNOS and up-regulation of inducible nitric oxide synthase (iNOS). Baicalein is the most abundant component that has anti-HIV, anti-tumor, anti-oxidant and free radical scavenging functions. In this present study, we shown that baicalein hinibits oxLDL-caused endothelial dysfunction through suppression of endothelial inflammation and oxidative stress that causes to cellular apoptosis. Specifically, baicalein reduces the elevation of ROS concentration, which subsequently inhibits the oxLDL-decreased expression of anti-oxidant enzymes, enriches the bioavailability of NO, stabilizes the mitochondrial membrane, thereby inhibiting the discharge of cytochrome c from mitochondria, a molecule required for the activation of the pro-apoptotic protein caspase 3. However, inhibition of eNOS impairs the anti-apoptotic and anti-inflammatory effects of baicalein. These results provide new insight into the possible molecular mechanisms by which baicalein protects against atherogenesis by NO-related pathways. PMID:27356749

  20. LDL hemoperfusion--a new procedure for LDL apheresis: biocompatibility results from a first pilot study in hypercholesterolemic atherosclerosis patients.

    PubMed

    Bosch, T; Schmidt, B; Kleophas, W; Otto, V; Samtleben, W

    1997-10-01

    Current lipid apheresis techniques can remove atherogenic lipoproteins only from plasma. The initial mandatory separation of plasma and blood cells renders the extracorporeal circuit complex. We recently described the first clinical application of a new lipid adsorber that adsorbs low-density lipoprotein (LDL) and lipoprotein (a) (Lp[a]) directly from whole blood. In continuation of our work, this paper describes the clinical biocompatibility of this new LDL hemoperfusion system. In a 2 center phase II clinical trial, 12 hypercholesterolemic patients suffering from overt coronary or peripheral artery disease were treated once with LDL hemoperfusion. The new LDL adsorber (DALI, Fresenius, St. Wendel, Germany) contained 480 ml of polyacrylate coated polyacrylamide gel. The anticoagulation protocol consisted of an initial heparin bolus followed by an acid citrate dextrose-A (ACD-A) infusion during the treatment. One patient blood volume was treated per session. All sessions were clinically uneventful. No signs of hemolysis or extracorporeal clot formation could be detected, and cell counts remained virtually constant. In a subgroup of patients (n = 4-6), further biocompatibility parameters were studied. Activation of leukocytes (elastase release), thrombocytes (beta-thromboglobulin [beta-TG] extrusion), and monocytes (interleukin (IL)-1beta and IL-6) were minimal. Complement activation (C3a and C5a generation) was negligible. The chosen anticoagulation protocol was both safe (constant ionized calcium levels) and effective (low thrombin-antithrombin formation). In summary, within the scope of a first pilot study, this new LDL hemoperfusion procedure combined the features of excellent clinical tolerance, good biocompatibility, and ease of handling. Phase III clinical trials will have to show whether these encouraging preliminary results can be corroborated in a larger patient population.

  1. Lipopolysaccharide augments the uptake of oxidized LDL by up-regulating lectin-like oxidized LDL receptor-1 in macrophages.

    PubMed

    Hossain, Ekhtear; Ota, Akinobu; Karnan, Sivasundaram; Takahashi, Miyuki; Mannan, Shahnewaj B; Konishi, Hiroyuki; Hosokawa, Yoshitaka

    2015-02-01

    There is a growing body of evidence supporting an intimate association of immune activation with the pathogenesis of cardiovascular diseases, including atherosclerosis. Uptake of oxidized low-density lipoprotein (oxLDL) through scavenging receptors promotes the formation of mature lipid-laden macrophages, which subsequently leads to exacerbation of regional inflammation and atherosclerotic plaque formation. In this study, we first examined changes in the mRNA level of the lectin-like oxLDL receptor-1 (LOX-1) in the mouse macrophage cell line RAW264.7 and the human PMA-induced macrophage cell line THP-1 after LPS stimulation. LPS significantly up-regulated LOX-1 mRNA in RAW264.7 cells; LOX-1 cell-surface protein expression was also increased. Flow cytometry and fluorescence microscopy analyses showed that cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with LPS stimulation. The augmented uptake of Dil-oxLDL was almost completely abrogated by treatment with an anti-LOX-1 antibody. Of note, knockdown of Erk1/2 resulted in a significant reduction of LPS-induced LOX-1 up-regulation. Treatment with U0126, a specific inhibitor of MEK, significantly suppressed LPS-induced expression of LOX-1 at both the mRNA and protein levels. Furthermore, LOX-1 promoter activity was significantly augmented by LPS stimulation; this augmentation was prevented by U0126 treatment. Similar results were also observed in human PMA-induced THP-1 macrophages. Taken together, our results indicate that LPS up-regulates LOX-1, at least in part through activation of the Erk1/2 signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of TLR4-mediated aberrant LOX-1 signaling in the pathogenesis of atherosclerosis.

  2. TRPM7 channel regulates ox-LDL-induced proliferation and migration of vascular smooth muscle cells via MEK-ERK pathways.

    PubMed

    Lin, Jinghan; Zhou, Shanshan; Zhao, Tingting; Ju, Ting; Zhang, Liming

    2016-02-01

    Transient receptor potential melastatin 7 (TRPM7) plays a key role in the pathophysiological response of multiple cell types. However, the role of TRPM7 channels in ox-LDL-induced proliferation and migration of VSMC remains unclear. This study used the thoracic aorta VSMCs to explore the effects of ox-LDL on cell proliferation and migration and to investigate the underlying molecular mechanisms and signaling pathways. Data demonstrated that ox-LDL significantly increased TRPM7 activity, and induced VSMC proliferation and migration. VSMC proliferation and migration were inhibited by nonspecific TRPM7 blocker 2-APB or synthetic siRNA targeting TRPM7. Furthermore, the phosphorylation of ERK1/2 and MEK1/2 associated with cell proliferation and migration decreased in TRPM7-deficient VSMC. Therefore, TRPM7 may constitute a useful target for the treatment of atherosclerosis. © 2016 Federation of European Biochemical Societies.

  3. The inhibitory effect of soy protein isolate on atherosclerosis in mice does not require the presence of LDL receptors or alteration of plasma lipoproteins.

    PubMed

    Adams, Michael R; Golden, Deborah L; Anthony, Mary S; Register, Thomas C; Williams, J Koudy

    2002-01-01

    The mechanisms by which dietary soy favorably influences lipoprotein metabolism and inhibits atherosclerosis are uncertain. Studies of blood mononuclear cells and cultured hepatocytes have indicated that certain soy peptides (i.e., 7S globulins) stimulate expression of LDL receptors. This pathway represents a hypothetical mechanism by which soy's hypocholesterolemic and antiatherosclerotic effects may be mediated. However, direct evidence supporting this hypothesis is lacking. To address this, we compared effects of dietary soy protein isolate in two genetically engineered mouse models of atherosclerosis. One mouse [LDL receptor -/- + apolipoprotein (apo) B transgenic] is devoid of LDL receptors and overproduces apolipoprotein B, whereas the other (apoE -/-) has a normal complement of LDL receptors but does not produce apolipoprotein E. Male (n = 10-12/group) and ovariectomized female (n = 10-12/group) mice were studied. There were three treatment groups, which differed principally by the source of the protein component of the diet: 1) casein/lactalbumin (no isoflavones), 2) alcohol-washed soy protein isolate (total isoflavones = 0.04 mg/g), and 3) intact soy protein isolate (total isoflavones = 1.72 mg/g). Atherosclerosis was assessed by quantifying the aortic content of esterified cholesterol. Atherosclerosis was inhibited (relative to the casein/lactalbumin group) by both alcohol-washed (45 and 31%) (P < 0.05) and intact (65 and 41%) (P < 0.05) soy protein isolate in LDL receptor -/- and apoE -/- mice, respectively. There was no sex difference. In a two-way analysis, there were significant effects of type of soy isolate and type of mouse. The antiatherosclerosis effect was enhanced in LDL receptor -/- mice (P < 0.001) and diminished in mice fed alcohol-washed soy protein isolate (P < 0.001). Furthermore, inhibitory effects of soy on atherosclerosis were unrelated to plasma LDL, VLDL or HDL cholesterol concentrations. The results represent direct evidence for the

  4. High concentrations of AGE-LDL and oxidized LDL in circulating immune complexes are associated with progression of retinopathy in type 1 diabetes.

    PubMed

    Lopes-Virella, Maria F; Baker, Nathaniel L; Hunt, Kelly J; Lyons, Timothy J; Jenkins, Alicia J; Virella, Gabriel

    2012-06-01

    To determine whether immunocomplexes (ICs) containing advanced glycation end product (AGE)-LDL (AGE-LDL) and oxidized LDL (oxLDL) contribute to the development of retinopathy over a 16-year period in subjects with type 1 diabetes. Levels of AGE-LDL and oxLDL in ICs were measured in 517 patients of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort. Retinopathy was assessed by stereoscopic fundus photography. Cox proportional hazards models were used to assess the effect of AGE-LDL-ICs and oxLDL-ICs on retinopathy progression. In unadjusted models, higher baseline levels of AGE-LDL-ICs and oxLDL-ICs significantly predicted progression of diabetic retinopathy outcomes. After adjustment by study-design variables (treatment group, retinopathy cohort, duration of type 1 diabetes, and baseline albumin excretion rate [AER], hemoglobin A(1c) (HbA(1c)), and Early Treatment Diabetic Retinopathy Study [ETDRS] score), one SD increase in IC levels was associated with 47% (hazard ratio [HR] 1.47 [95% CI 1.19-1.81]; AGE-LDL-IC) and 45% (1.45 [1.17-1.80]; oxLDL-IC) increased risk of developing proliferative diabetic retinopathy (PDR) and 37% (1.37 [1.12-1.66]; to both ICs) increased risk of progressing to severe nonproliferative retinopathy. Analyses were stratified by retinopathy cohort because results differed between primary and secondary cohorts. For AGE-LDL-ICs, HR for progression to PDR was 2.38 (95% CI 1.30-4.34) in the primary cohort and attenuated in the secondary cohort (1.29 [1.03-1.62]). Similar results were observed for oxLDL-ICs. Increased levels of AGE-LDL and oxLDL in ICs are associated with increased risk for progression to advanced retinopathy in patients with type 1 diabetes, indicating that the antibody response to modified LDL plays a significant role in retinopathy progression.

  5. Smallest LDL particles are most strongly related to coronarydisease progression in men

    SciTech Connect

    Williams, Paul T.; Superko, H. Robert; Haskell, William L.; Alderman, Edwin L.; Blanche, Patricia J.; Holl, Laura Glines; Krauss,Ronald M.

    2002-12-03

    Objective-LDLs include particle subclasses that havedifferent mobilities on polyacrylamide gradient gels: LDL-I (27.2to 28.5nm), LDL-IIa (26.5 to 27.2 nm), LDL-IIb (25.6 to 26.5 nm), LDL-IIIa (24.7to 25.6 nm), LDL-IIIb (24.2 to 24.7nm), LDL-IVa (23.3 to 24.2 nm), andLDL-IVb (22.0 to 23.3 nm in diameter). We hypothesized that theassociationbetween smaller LDL particles and coronary artery disease(CAD) risk might involve specific LDL subclasses.Methods andResults-Average 4-year onstudy lipoprotein measurements were comparedwith annualized rates of stenosischange from baseline to 4 years in 117men with CAD. The percentages of total LDL and HDL occurringwithinindividual subclasses were measured by gradient gelelectrophoresis. Annual rate of stenosis change was relatedconcordantlyto onstudy averages of total cholesterol (P 0.04), triglycerides (P0.05), VLDL mass (P 0.03),total/HDL cholesterol ratio (P 0.04), LDL-IVb(P 0.01), and HDL3a (P 0.02) and inversely to HDL2-mass (P 0.02)and HDL2b(P 0.03). The average annual rate in stenosis change was 6-fold morerapid in the fourth quartile ofLDL-IVb (5.2 percent) than in the firstquartile ( 2.5 percent, P 0.03). Stepwise multiple regression analysisshowed thatLDL-IVb was the single best predictor of stenosischange.Conclusions-LDL-IVb was the single best lipoprotein predictor ofincreased stenosis, an unexpected result, given thatLDL-IVb representsonly a minor fraction of total LDL. (Arterioscler Thromb Vasc Biol.2003;23:314-321.)

  6. Unique cellular events occurring during the initial interaction of macrophages with matrix-retained or methylated aggregated low density lipoprotein (LDL). Prolonged cell-surface contact during which ldl-cholesteryl ester hydrolysis exceeds ldl protein degradation.

    PubMed

    Buton, X; Mamdouh, Z; Ghosh, R; Du, H; Kuriakose, G; Beatini, N; Grabowski, G A; Maxfield, F R; Tabas, I

    1999-11-05

    A critical event in atherogenesis is the interaction of arterial wall macrophages with subendothelial lipoproteins. Although most studies have investigated this interaction by incubating cultured macrophages with monomeric lipoproteins dissolved in media, arterial wall macrophages encounter lipoproteins that are mostly bound to subendothelial extracellular matrix, and these lipoproteins are often aggregated or fused. Herein, we utilize a specialized cell-culture system to study the initial interaction of macrophages with aggregated low density lipoprotein (LDL) bound to extracellular matrix. The aggregated LDL remains extracellular for a relatively prolonged period of time and becomes lodged in invaginations in the surface of the macrophages. As expected, the degradation of the protein moiety of the LDL was very slow. Remarkably, however, hydrolysis of the cholesteryl ester (CE) moiety of the LDL was 3-7-fold higher than that of the protein moiety, in stark contrast to the situation with receptor-mediated endocytosis of acetyl-LDL. Similar results were obtained using another experimental system in which the degradation of aggregated LDL protein was delayed by LDL methylation rather than by retention on matrix. Additional experiments indicated the following properties of this interaction: (a) LDL-CE hydrolysis is catalyzed by lysosomal acid lipase; (b) neither scavenger receptors nor the LDL receptor appear necessary for the excess LDL-CE hydrolysis; and (c) LDL-CE hydrolysis in this system is resistant to cellular potassium depletion, which further distinguishes this process from receptor-mediated endocytosis. In summary, experimental systems specifically designed to mimic the in vivo interaction of arterial wall macrophages with subendothelial lipoproteins have demonstrated an initial period of prolonged cell-surface contact in which CE hydrolysis exceeds protein degradation.

  7. Outdoor temperature is associated with serum HDL and LDL

    PubMed Central

    Halonen, Jaana I.; Zanobetti, Antonella; Sparrow, David; Vokonas, Pantel S.; Schwartz, Joel

    2015-01-01

    Background While exposures to high and low air temperatures are associated with cardiovascular mortality, the underlying mechanisms are poorly understood. The risk factors for cardiovascular disease include high levels of total cholesterol and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL). We investigated whether temperature was associated with changes in circulating lipid levels, and whether this might explain part of the association with increased cardiovascular events. Methods The study cohort consisted of 478 men in the greater Boston area with a mean age of 74.2 years. They visited the clinic every 3–5 years between 1995–2008 for physical examination and to complete questionnaires. We excluded from analyses all men taking statin medication and all days with missing data, resulting in a total of 862 visits. Associations between three temperature variables (ambient, apparent, and dew point temperature) and serum lipid levels (total cholesterol, HDL, LDL, and triglycerides) were studied with linear mixed models that included possible confounders such as air pollution and a random intercept for each subject. Results We found that HDL decreased −1.76% (95% CI: −3.17 – −0.32, lag 2 days), and −5.58% (95% CI: −8.87 – −2.16, moving average of 4 weeks) for each 5°C increase in mean ambient temperature. For the same increase in mean ambient temperature, LDL increased by 1.74% (95% CI: 0.07 – 3.44, lag 1 day) and 1.87% (95% CI: 0.14 – 3.63, lag 2 days). These results were also similar for apparent and dew point temperatures. No changes were found in total cholesterol or triglycerides in relation to temperature increase. Conclusions Changes in HDL and LDL levels associated with an increase in ambient temperature may be among the underlying mechanisms of temperature-related cardiovascular mortality. PMID:21172696

  8. Immunization with malondialdehyde-modified low-density lipoprotein (LDL) reduces atherosclerosis in LDL receptor-deficient mice challenged with Porphyromonas gingivalis.

    PubMed

    Turunen, S Pauliina; Kummu, Outi; Wang, Chunguang; Harila, Kirsi; Mattila, Riikka; Sahlman, Marjo; Pussinen, Pirkko J; Hörkkö, Sohvi

    2015-05-01

    Periodontal infections increase the risk of atherosclerotic vascular disease via partly unresolved mechanisms. Of the natural IgM Abs that recognize molecular mimicry on bacterial epitopes and modified lipid and protein structures, IgM directed against oxidized low-density lipoprotein (LDL) is associated with atheroprotective properties. Here, the effect of natural immune responses to malondialdehyde-modified LDL (MDA-LDL) in conferring protection against atherosclerosis, which was accelerated by the major periodontopathogen Porphyromonas gingivalis, was investigated. LDL receptor-deficient (LDLR(-/-)) mice were immunized with mouse MDA-LDL without adjuvant before topical application challenge with live P. gingivalis. Atherosclerosis was analyzed after a high-fat diet, and plasma IgG and IgM Ab levels were measured throughout the study, and the secretion of IL-5, IL-10 and IFN-γ in splenocytes stimulated with MDA-LDL was determined. LDLR(-/-) mice immunized with MDA-LDL had elevated IgM and IgG levels to MDA-LDL compared with saline-treated controls. MDA-LDL immunization diminished aortic lipid depositions after challenge with P. gingivalis compared with mice receiving only P. gingivalis challenge. Immunization of LDLR(-/-) mice with homologous MDA-LDL stimulated the production of IL-5, implicating general activation of B-1 cells. Immune responses to MDA-LDL protected from the P. gingivalis-accelerated atherosclerosis. Thus, the linkage between bacterial infectious burden and atherogenesis is suggested to be modulated via natural IgM directed against cross-reactive epitopes on bacteria and modified LDL. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  9. Antioxydant activity of β-carboline derivatives in the LDL oxidation model.

    PubMed

    Hadjaz, Fariza; Besret, Soizic; Martin-Nizard, Françoise; Yous, Saïd; Dilly, Sébastien; Lebegue, Nicolas; Chavatte, Philippe; Duriez, Patrick; Berthelot, Pascal; Carato, Pascal

    2011-06-01

    A series of β-carboline compounds were synthesized, starting from compound GWC22, their antioxidant activity was determined by inhibition of lipid peroxidation. The oxidation of LDL was induced in the presence of CuSO4 or 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH). The protective actions of these compounds against the cytotoxicity were evaluated with lactate dehydrogenase (LDH) activity in bovine aortic endothelial cells (BAECs) and cellular vitality by measuring mitochondrial activity in the presence of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide). Most of compounds showed an higher antioxidant activity than GWC22 derivative (R=1.6 for 5 μM CuSO4). The best antioxidant activities are phenolic and benzyloxy derivatives with ratio R=1.9 to 2.8 for 1 μM CuSO4. These substances have protective actions and increase significantly the cell viability.

  10. [PCSK-9 inhibitors, effects on LDL-C and future implications: What you should know].

    PubMed

    Corral, P; Ruiz, A J

    2017-07-11

    The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions. The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

  11. Molecular basis for LDL receptor recognition by PCSK9.

    PubMed

    Kwon, Hyock Joo; Lagace, Thomas A; McNutt, Markey C; Horton, Jay D; Deisenhofer, Johann

    2008-02-12

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) posttranslationally regulates hepatic low-density lipoprotein receptors (LDLRs) by binding to LDLRs on the cell surface, leading to their degradation. The binding site of PCSK9 has been localized to the epidermal growth factor-like repeat A (EGF-A) domain of the LDLR. Here, we describe the crystal structure of a complex between PCSK9 and the EGF-A domain of the LDLR. The binding site for the LDLR EGF-A domain resides on the surface of PCSK9's subtilisin-like catalytic domain containing Asp-374, a residue for which a gain-of-function mutation (Asp-374-Tyr) increases the affinity of PCSK9 toward LDLR and increases plasma LDL-cholesterol (LDL-C) levels in humans. The binding surface on PCSK9 is distant from its catalytic site, and the EGF-A domain makes no contact with either the C-terminal domain or the prodomain. Point mutations in PCSK9 that altered key residues contributing to EGF-A binding (Arg-194 and Phe-379) greatly diminished binding to the LDLR's extracellular domain. The structure of PCSK9 in complex with the LDLR EGF-A domain defines potential therapeutic target sites for blocking agents that could interfere with this interaction in vivo, thereby increasing LDLR function and reducing plasma LDL-C levels.

  12. Sequential change in physicochemical properties of LDL during oxidative modification.

    PubMed

    Kido, Toshimi; Kondo, Kazuo; Itakura, Hiroshige; Yokoyama, Shinji

    2015-12-01

    Oxidized LDL is thought to be a highly atherogenic lipoprotein. Structural background of this pathogenesis, however, has not yet been well defined. Physicochemical characterization of this lipoprotein is still controversial, which therefore makes it difficult to take a mechanistic approach to its atherogenicity. We thus conducted investigation of time-dependent changes in chemical compositions and alternation of physical properties of LDL in detail during its oxidation induced by human embryonic endothelial cells and copper ions. The oxidation caused hydrolysis of glycerolipids being demonstrated as decrease of triglyceride and choline-phospholipid and increase of lysophosphatidylcholine. Fragmentation of apoB was also induced while over-all protein components stayed with the particles. The density of the particles continuously shifted to higher fractions for all the particles to reach d ≥ 1.044 after 10h incubation. The average diameter of LDL, however, decreased from 28.1 nm to 25.6 nm by 5h and increased to 27.1 nm towards 20 h incubation with the increase of discoid particles. These dynamic changes can be interpreted by losing fatty acyl group from the core lipid components perhaps due to oxidative degradation and by increase of surface lysophosphatidylcholine to cause remodeling of the particles. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  13. Human LDL Structural Diversity Studied by IR Spectroscopy

    PubMed Central

    Fernández-Higuero, José A.; Salvador, Ana M.; Martín, Cesar; Milicua, José Carlos G.; Arrondo, José L. R.

    2014-01-01

    Lipoproteins are responsible for cholesterol traffic in humans. Low density lipoprotein (LDL) delivers cholesterol from liver to peripheral tissues. A misleading delivery can lead to the formation of atherosclerotic plaques. LDL has a single protein, apoB-100, that binds to a specific receptor. It is known that the failure associated with a deficient protein-receptor binding leads to plaque formation. ApoB-100 is a large single lipid-associated polypeptide difficulting the study of its structure. IR spectroscopy is a technique suitable to follow the different conformational changes produced in apoB-100 because it is not affected by the size of the protein or the turbidity of the sample. We have analyzed LDL spectra of different individuals and shown that, even if there are not big structural changes, a different pattern in the intensity of the band located around 1617 cm−1 related with strands embedded in the lipid monolayer, can be associated with a different conformational rearrangement that could affect to a protein interacting region with the receptor. PMID:24642788

  14. Impaired oxidant/antioxidant status and LDL-fatty acid composition are associated with increased susceptibility to peroxidation of LDL in diabetic patients.

    PubMed

    Merzouk, S; Hichami, A; Sari, A; Madani, S; Merzouk, H; Yahia Berrouiguet, A; Lenoir-Rousseaux, J J; Chabane-Sari, N; Khan, N A

    2004-12-01

    This study was carried out to determine the relationships between oxidant/antioxidant status, in vitro LDL oxidizability and LDL-fatty acid composition in diabetes mellitus. Plasma total antioxidant capacity (oxygen radical absorbance capacity, ORAC) and LDL-cholesteryl ester fatty acids were investigated in type 1 and type 2 diabetic subjects with and without complications. The degree of LDL oxidation was determined by the measurement of hydroperoxide levels before and after in vitro peroxidative stress with CuSO4. ORAC values were decreased in diabetic subjects who showed high basal hydroperoxide levels. Oxidizability of LDL in these subjects was higher than in control subjects and it was unrelated to LDL-fatty acid composition. However, in type 2 diabetic subjects with complications, alterations in LDL-fatty acid composition were associated with their enhanced oxidative susceptibility. LDL-fatty acid alterations might be an additional factor that influences LDL oxidizability especially in type 2 diabetes. In conclusion, diabetes mellitus is associated with enhanced oxidative stress and defective antioxidant/oxidant balance regardless the type of diabetes and presence of complications.

  15. Enhancement of macrophage survival and DNA synthesis by oxidized-low-density-lipoprotein (LDL)-derived lipids and by aggregates of lightly oxidized LDL.

    PubMed Central

    Hamilton, J A; Jessup, W; Brown, A J; Whitty, G

    2001-01-01

    Human atherosclerotic plaque contains a partially characterized range of normal and oxidized lipids formed mainly from free and esterified cholesterol and phospholipids, some of which can be located in macrophage-derived "foam" cells. Oxidation of low-density lipoprotein (LDL) is often considered as an important event leading to subsequent foam-cell development, which may also include enhanced cell survival and/or proliferation. The active component(s) in oxidized LDL (ox.LDL) causing macrophage proliferation is debated. We report here that the lipid component of ox.LDL can promote macrophage survival and DNA synthesis, the latter response showing a synergistic effect in the presence of low concentrations of macrophage colony-stimulating factor. 7-Ketocholesterol showed some stimulation of macrophage DNA synthesis whereas hypochlorite-oxidized (i.e. apolipoprotein B-oxidized) LDL did not. Plaque-derived lipids could enhance macrophage survival. It has not been proven that LDL in lesions is oxidized sufficiently to be the dominant source of sterols in vivo or to be able to induce macrophage growth in vitro or in vivo; it has been suggested that aggregation of modified LDL in vivo is an important step in the deposition of intracellular lipid. We found that aggregation of lightly oxidized LDL potentiated dramatically its ability to stimulate macrophage DNA synthesis, indicating that extensive oxidation of LDL is not required for this response in vitro and perhaps in vivo. PMID:11256965

  16. Uptake and Trafficking of Mildly Oxidized LDL and Acetylated LDL in THP-1 Cells Does Not Explain the Differences in Lysosomal Metabolism of These Two Lipoproteins

    NASA Astrophysics Data System (ADS)

    Yancey, Patricia G.; Miles, Stacia; Schwegel, Jennifer; Gray Jerome, W.

    2002-04-01

    Foam cells in the atherosclerotic lesion have substantial cholesterol stores within large, swollen lysosomes. This feature is mimicked by incubating THP-1 macrophages with mildly oxidized low density lipoprotein (LDL). Incubation of THP-1 cells with acetylated LDL produces cytoplasmic cholesteryl ester accumulation rather than lysosomal storage. The differences could be due to differences in uptake and delivery of lipoprotein to lysosomes or to lysosomal and post-lysosomal processing events. We compared uptake and lysosomal trafficking of acetylated and oxidized LDL using colloidal gold-labeled lipoproteins. Labeling did not alter cellular cholesterol accumulation. We found that uptake and delivery to lysosomes are not different for acetylated and oxidized LDL. In fact, both oxidized and acetylated LDL can be delivered to the same lysosomes. Sequential incubation with oxidized LDL followed by acetylated LDL showed that the lipid-engorged lysosomes are long-lived structures, continuously accepting newly ingested lipoprotein. Comparison of acetylated and oxidized LDL in mouse peritoneal macrophages, a cell which does not accumulate substantial lysosomal lipid, also revealed no differences in uptake. This indicates that in THP-1 cells, the differences in metabolism of oxidized and acetylated LDL are due to cell-specific lysosomal or post-lysosomal events not present in B6C3F1 mouse macrophages.

  17. Influence of valence, electronegativity, atomic radii, and crest-trough interaction with phonons on the high-temperature copper oxide superconductors

    SciTech Connect

    Pauling, L.

    1987-07-13

    Several structural features, including electron transfer between atoms of different electronegativity, oxygen deficiency, and unsynchronized resonance of valence bonds, as well as tight binding of atoms and the presence of both hypoelectronic and hyperelectronic elements, cooperatre to confer metallic properties and high-temperature superconductivity on compounds such as (Sr,Ba,Y,La)/sub 2/CuO/sub 4-//sub y/. .AE

  18. Collisionless damping of dust-acoustic waves in a charge varying electronegative dusty plasma with nonthermal ions

    NASA Astrophysics Data System (ADS)

    Benzekka, Moufida; Tribeche, Mouloud

    2016-07-01

    The aim of the present communication is to investigate the charge variation induced nonlinear dust acoustic wave damping in a charge varying electronegative dusty plasma with nonthermal ions. It is shown that the collisionless damping due to dust charge fluctuation causes the nonlinear dust acoustic wave propagation to be described by a damped Korteweg-de Vries equation (dK-dV). The latter is significantly modified by the nonthermal negative ions effects. It may be useful to note that we consider nonthermal negative ions because of the role of their distribution into the formation and dynamics of nonlinear dust acoustic structures. Moreover, the observation of nonthermal ion distributions made by Phobos and Nozomi motivated us to consider non- Maxwellian ions.

  19. Dissipative dust-acoustic shock waves in a varying charge electronegative magnetized dusty plasma with trapped electrons

    NASA Astrophysics Data System (ADS)

    Bacha, Mustapha; Tribeche, Mouloud

    2016-08-01

    The combined effects of an oblique magnetic field and electron trapping on dissipative dust-acoustic waves are examined in varying charge electronegative dusty plasmas with application to the Halley Comet plasma (˜104 km from the nucleus). A weakly nonlinear analysis is carried out to derive a modified Korteweg-de Vries-Burger-like equation. Making use of the equilibrium current balance equation, the physically admissible values of the electron trapping parameter are first constrained. We then show that the Burger dissipative term is solely due to the dust charge variation process. It is found that an increase of the magnetic field obliqueness or a decrease of its magnitude renders the shock structure more dispersive.

  20. Dissipative dust-acoustic shock waves in a varying charge electronegative magnetized dusty plasma with trapped electrons

    SciTech Connect

    Bacha, Mustapha; Tribeche, Mouloud E-mail: mtribeche@usthb.dz

    2016-08-15

    The combined effects of an oblique magnetic field and electron trapping on dissipative dust-acoustic waves are examined in varying charge electronegative dusty plasmas with application to the Halley Comet plasma (∼10{sup 4} km from the nucleus). A weakly nonlinear analysis is carried out to derive a modified Korteweg-de Vries-Burger-like equation. Making use of the equilibrium current balance equation, the physically admissible values of the electron trapping parameter are first constrained. We then show that the Burger dissipative term is solely due to the dust charge variation process. It is found that an increase of the magnetic field obliqueness or a decrease of its magnitude renders the shock structure more dispersive.

  1. Improved Carbohydrate Metabolism After Bariatric Surgery Raises Antioxidized LDL Antibody Levels in Morbidly Obese Patients

    PubMed Central

    Garrido-Sánchez, Lourdes; García-Almeida, Jose M.; García-Serrano, Sara; Cardona, Isabel; García-Arnes, Juan; Soriguer, Federico; Tinahones, Francisco J.; García-Fuentes, Eduardo

    2008-01-01

    OBJECTIVE—Antioxidized LDL (anti-oxLDL) antibodies have recently been suggested to be protective against the development of diabetes. We measured the changes in anti-oxLDL antibody levels in the inverse situation of improvement in carbohydrate metabolism. RESEARCH DESIGN AND METHODS—The study was undertaken in 73 morbidly obese individuals, 21 of whom had type 2 diabetes, before and 7 months after they underwent bariatric surgery and in 11 healthy, nonobese individuals. Measurements were made of the area under the curve of glucose (AUCGlu) by an intravenous glucose tolerance test and of oxidized LDL (oxLDL) and IgG and IgM anti-oxLDL antibodies. RESULTS—The morbidly obese patients with diabetes had significantly higher levels of oxLDL compared with the morbidly obese patients with normal fasting glucose and the control subjects and significantly lower levels of IgM anti-oxLDL antibodies. An inverse correlation was found between the levels of oxLDL and IgM anti-oxLDL antibodies (r = −0.352, P = 0.012). Although the levels of IgG and IgM anti-oxLDL antibodies rose after surgery, this increase was only significant in the diabetic patients, who experienced an improvement in their metabolic profile. Different multiple linear regression models showed that the AUCGlu was the main factor explaining the behavior of the levels of oxLDL and anti-oxLDL antibodies. CONCLUSIONS—We found a close association between carbohydrate metabolism and IgM anti-oxLDL antibodies, which were significantly reduced in the morbidly obese patients with diabetes. The improvement in carbohydrate metabolism after bariatric surgery led to a significant increase in the levels of IgG and IgM anti-oxLDL antibodies. PMID:18835956

  2. Improved carbohydrate metabolism after bariatric surgery raises antioxidized LDL antibody levels in morbidly obese patients.

    PubMed

    Garrido-Sánchez, Lourdes; García-Almeida, Jose M; García-Serrano, Sara; Cardona, Isabel; García-Arnes, Juan; Soriguer, Federico; Tinahones, Francisco J; García-Fuentes, Eduardo

    2008-12-01

    Antioxidized LDL (anti-oxLDL) antibodies have recently been suggested to be protective against the development of diabetes. We measured the changes in anti-oxLDL antibody levels in the inverse situation of improvement in carbohydrate metabolism. The study was undertaken in 73 morbidly obese individuals, 21 of whom had type 2 diabetes, before and 7 months after they underwent bariatric surgery and in 11 healthy, nonobese individuals. Measurements were made of the area under the curve of glucose (AUC(Glu)) by an intravenous glucose tolerance test and of oxidized LDL (oxLDL) and IgG and IgM anti-oxLDL antibodies. The morbidly obese patients with diabetes had significantly higher levels of oxLDL compared with the morbidly obese patients with normal fasting glucose and the control subjects and significantly lower levels of IgM anti-oxLDL antibodies. An inverse correlation was found between the levels of oxLDL and IgM anti-oxLDL antibodies (r = -0.352, P = 0.012). Although the levels of IgG and IgM anti-oxLDL antibodies rose after surgery, this increase was only significant in the diabetic patients, who experienced an improvement in their metabolic profile. Different multiple linear regression models showed that the AUC(Glu) was the main factor explaining the behavior of the levels of oxLDL and anti-oxLDL antibodies. We found a close association between carbohydrate metabolism and IgM anti-oxLDL antibodies, which were significantly reduced in the morbidly obese patients with diabetes. The improvement in carbohydrate metabolism after bariatric surgery led to a significant increase in the levels of IgG and IgM anti-oxLDL antibodies.

  3. Effects of Different Simple Triglycerides on Cell Fatty Acid Compositions, Proliferation-Related Protein, and Gene Expressions Induced by Oxidized-LDL in HUVSMCs.

    PubMed

    Li, Hongyan; Pan, Yao; Luo, Kaiyun; Luo, Ting; Fan, Yawei; Deng, Zeyuan

    2017-02-01

    The proliferating effects of 3 different simple triglycerides (tristearin, triolein, and trilinolein) on the human umbilical vein smooth muscle cells (HUVSMCs) induced by oxidized-LDL (ox-LDL) were investigated in this study. The protein and mRNA gene expressions of proliferating cell nuclear antigen (PCNA), smooth muscle-α-actin (SM-α-actin), and monocyte chemoattractant protein-1 (MCP-1) in HUVSMCs were measured by Western blotting and real-time quantitative polymerase chain reaction (PCR). It was shown that in tristearin (SSS) treated HUVSMCs, the saturated fatty acid content was increased, and the compositions of polyunsaturated fatty acid (PUFA) and monounsaturated fatty acid were decreased significantly. On the other hand, triolein (OOO) and trilinolein (LLL) significantly increased the levels of some typical PUFA such as arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid. Moreover, LLL and OOO could upregulate the protein and mRNA expressions of PCNA, MCP-1 as well as downregulate the expression of SM-α-actin. The results also showed that, SSS had significant promotion effects on the proliferation of HUVSMCs induced by ox-LDL. Although both LLL and OOO could inhibit the proliferation of HUVSMCs induced by ox-LDL, and might have certain inhibition of the atherosclerotic process.

  4. LOX-1 expression and oxidized LDL uptake and toxicity in the HN33 neuronal cell line.

    PubMed

    Mao, Xiaoou; Xie, Lin; Greenberg, David A

    2014-09-19

    Cardiovascular risk factors appear to influence the risk and progression of neurodegenerative disease, but the mechanisms involved are poorly understood. We investigated the possible involvement of oxidized low-density lipoprotein receptor (LOX-1) and oxidized low-density lipoprotein (Ox-LDL) in neurodegeneration by studying the expression of LOX-1 and the effects of Ox-LDL in HN33 cells, a neuronal cell line of central nervous system origin. HN33 cells showed LOX-1 protein expression, hypoxic induction of LOX-1, Ox-LDL uptake and Ox-LDL toxicity. LOX-1/Ox-LDL signaling may contribute to the association between cardiovascular risk factors and neurodegenerative disease.

  5. HDL particles from type 1 diabetic patients are unable to reverse the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation.

    PubMed

    Perségol, L; Foissac, M; Lagrost, L; Athias, A; Gambert, P; Vergès, B; Duvillard, L

    2007-11-01

    In healthy individuals, HDL can counteract the inhibition of vasorelaxation induced by oxidised LDL. Several abnormalities such as increased size, glycation and decreased paraoxonase activity have been reported for HDL from type 1 diabetic patients. Thus, we hypothesised that the ability of HDL to protect vessels against impairments of vasorelaxation would be decreased in these patients. We compared the ability of HDL from 18 type 1 diabetic patients and 12 control participants to counteract the inhibition of endothelium-dependent relaxation induced by oxidised LDL on rabbit aorta rings. Serum triacylglycerol and total cholesterol, LDL- and HDL-cholesterol were similar in type 1 diabetic and control participants. Fasting glycaemia and the HDL-fructosamine level were higher in diabetic patients than in controls (9.06 +/- 3.55 vs 5.27 +/- 0.23 mmol/l, p < 0.005; and 10.2 +/- 3.2 vs 7.7 +/- 2.5 micromol/g protein, p < 0.05, respectively). HDL composition, size and paraoxonase activity were similar in both groups. HDL from controls reduced the inhibitory effect of oxidised LDL on maximal relaxation (E (max); 79.3 +/- 11.8 vs 66.4 +/- 11.7%, p < 0.05), whereas HDL from type 1 diabetic patients had no effect (E (max) = 70.6 +/- 17.4 vs 63.9 +/- 17.2%, NS). In type 1 diabetic patients, E (max) was not correlated with glycaemia or the HDL-fructosamine level. HDL particles from type 1 diabetic patients do not protect against inhibition of endothelium-dependent vasorelaxation induced by oxidised LDL, in contrast to HDL particles from healthy individuals. This defect cannot be explained by abnormalities in HDL composition, size or paraoxonase activity, and may contribute to the early development of atherosclerotic lesions in type 1 diabetic patients.

  6. Immunoregulation by low density lipoproteins in man. Inhibition of mitogen-induced T lymphocyte proliferation by interference with transferrin metabolism.

    PubMed Central

    Cuthbert, J A; Lipsky, P E

    1984-01-01

    Human low density lipoprotein (LDL, d = 1.020-1.050 g/ml) inhibits mitogen-stimulated T lymphocyte DNA synthesis. Because both LDL and transferrin bind to specific cell surface receptors and enter cells by the similar means of receptor-mediated endocytosis, and because transferrin is necessary for lymphocyte DNA synthesis, we investigated the possibility that LDL may inhibit mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL inhibited mitogen-stimulated lymphocyte [3H]thymidine incorporation in a concentration-dependent manner. The degree of inhibition was most marked in serum-free cultures, but was also observed in serum-containing cultures. The addition of transferrin not only augmented mitogen-induced lymphocyte [3H]thymidine incorporation in serum-free medium but also completely reversed the inhibitory effect of LDL in both serum-free and serum-containing media. Similar results were obtained when lymphocyte proliferation was assayed by counting the number of cells in culture. Transferrin also reversed the inhibition of lymphocyte responses caused by very low density lipoproteins and by cholesterol. The ability of transferrin to reverse the inhibitory effect of lipoproteins was specific, in that native but not denatured transferrin was effective whereas a variety of other proteins were ineffective. These results indicate that LDL inhibits mitogen-stimulated lymphocyte responses by interfering with transferrin metabolism. LDL only inhibited lymphocyte responses after a 48-h incubation if present from the initiation of the culture. By contrast, transferrin reversed inhibition when added after 24 h of the 48-h incubation. LDL did not inhibit lymphocyte responses by nonspecifically associating with transferrin. In addition, the acquisition of specific lymphocyte transferrin receptors was not blocked by LDL. Moreover, transferrin did not prevent the binding and uptake of fluorescent-labeled LDL by activated lymphocytes

  7. Genome-wide RNAi screen reveals ALK1 mediates LDL uptake and transcytosis in endothelial cells

    PubMed Central

    Kraehling, Jan R.; Chidlow, John H.; Rajagopal, Chitra; Sugiyama, Michael G.; Fowler, Joseph W.; Lee, Monica Y.; Zhang, Xinbo; Ramírez, Cristina M.; Park, Eon Joo; Tao, Bo; Chen, Keyang; Kuruvilla, Leena; Larriveé, Bruno; Folta-Stogniew, Ewa; Ola, Roxana; Rotllan, Noemi; Zhou, Wenping; Nagle, Michael W.; Herz, Joachim; Williams, Kevin Jon; Eichmann, Anne; Lee, Warren L.; Fernández-Hernando, Carlos; Sessa, William C.

    2016-01-01

    In humans and animals lacking functional LDL receptor (LDLR), LDL from plasma still readily traverses the endothelium. To identify the pathways of LDL uptake, a genome-wide RNAi screen was performed in endothelial cells and cross-referenced with GWAS-data sets. Here we show that the activin-like kinase 1 (ALK1) mediates LDL uptake into endothelial cells. ALK1 binds LDL with lower affinity than LDLR and saturates only at hypercholesterolemic concentrations. ALK1 mediates uptake of LDL into endothelial cells via an unusual endocytic pathway that diverts the ligand from lysosomal degradation and promotes LDL transcytosis. The endothelium-specific genetic ablation of Alk1 in Ldlr-KO animals leads to less LDL uptake into the aortic endothelium, showing its physiological role in endothelial lipoprotein metabolism. In summary, identification of pathways mediating LDLR-independent uptake of LDL may provide unique opportunities to block the initiation of LDL accumulation in the vessel wall or augment hepatic LDLR-dependent clearance of LDL. PMID:27869117

  8. LDL particle core enrichment in cholesteryl oleate increases proteoglycan binding and promotes atherosclerosis[S

    PubMed Central

    Melchior, John T.; Sawyer, Janet K.; Kelley, Kathryn L.; Shah, Ramesh; Wilson, Martha D.; Hantgan, Roy R.; Rudel, Lawrence L.

    2013-01-01

    Several studies in humans and animals suggest that LDL particle core enrichment in cholesteryl oleate (CO) is associated with increased atherosclerosis. Diet enrichment with MUFAs enhances LDL CO content. Steroyl O-acyltransferase 2 (SOAT2) is the enzyme that catalyzes the synthesis of much of the CO found in LDL, and gene deletion of SOAT2 minimizes CO in LDL and protects against atherosclerosis. The purpose of this study was to test the hypothesis that the increased atherosclerosis associated with LDL core enrichment in CO results from an increased affinity of the LDL particle for arterial proteoglycans. ApoB-100-only Ldlr−/− mice with and without Soat2 gene deletions were fed diets enriched in either cis-MUFA or n-3 PUFA, and LDL particles were isolated. LDL:proteogylcan binding was measured using surface plasmon resonance. Particles with higher CO content consistently bound with higher affinity to human biglycan and the amount of binding was shown to be proportional to the extent of atherosclerosis of the LDL donor mice. The data strongly support the thesis that atherosclerosis was induced through enhanced proteoglycan binding of LDL resulting from LDL core CO enrichment. PMID:23804810

  9. Achievement of LDL-C goals depends on baseline LDL-C and choice and dose of statin: an analysis from the VOYAGER database.

    PubMed

    Palmer, Mike K; Nicholls, Stephen J; Lundman, Pia; Barter, Philip J; Karlson, Björn W

    2013-12-01

    Reducing low-density lipoprotein cholesterol (LDL-C) levels decreases cardiovascular risk in direct proportion to the decrease in LDL-C. The aim of this study was to assess the importance of baseline LDL-C and choice and dose of statin in achievement of LDL-C goals of 100 and 70 mg/dl, using a novel statistical model. The analysis included 30,102 patient exposures to rosuvastatin 10-40 mg or atorvastatin 10-80 mg from 31 direct comparative trials in the VOYAGER database. For each statin dose, percentage goal achievement was plotted for 20 equally large subgroups defined by baseline LDL-C. Logistic regression analysis was then performed for each statin dose to estimate the percentage of patients reaching target. Best-fit logistic regression curves were plotted 'pair-wise', comparing each rosuvastatin dose with equal or higher doses of atorvastatin. LDL-C <100 mg/dl was achieved by 53.7-85.5% of patients on rosuvastatin 10-40 mg and 43.3-80.0% of those on atorvastatin 10-80 mg, whereas LDL-C <70 mg/dl was achieved by 4.5-44.0% of rosuvastatin-treated patients and 6.5-41.4% of those on atorvastatin. Similar differences in efficacy favouring rosuvastatin over equal or double doses of atorvastatin were observed across the range of baseline LDL-C levels for both LDL-C goals, being more pronounced at higher baseline values. Baseline LDL-C and choice and dose of statin are important for LDL-C goal achievement. The present analysis may allow prediction of individual patient response to different statins at different doses.

  10. The role of vascular peroxidase 1 in ox-LDL-induced vascular smooth muscle cell calcification.

    PubMed

    Tang, Yixin; Xu, Qian; Peng, Haiyang; Liu, Zhaoya; Yang, Tianlun; Yu, Zaixin; Cheng, Guangjie; Li, Xiaohui; Zhang, Guogang; Shi, Ruizheng

    2015-12-01

    Reactive oxygen species (ROS)-induced osteogenic differentiation of vascular smooth muscle cells (VSMCs) is associated with the pathogenesis of vascular calcification. Vascular peroxidase 1 (VPO1), a peroxidase in the cardiovascular system, utilizes the hydrogen peroxide (H2O2) produced by co-expressed NADPH oxidases to produce hypochlorous acid (HOCl) and catalyze peroxidative reactions. The aim of this study was to determine whether VPO1 plays a role in the osteogenic differentiation of VSMCs in the setting of the vascular calcification induced by oxidized low-density lipoprotein (ox-LDL). In cultured primary rat VSMCs, we observed that the expression of VPO1 was significantly increased in combination with increases in calcification, as demonstrated via increased mineralization, as well as increased alkaline phosphatase (ALP) activity and up-regulated runt-related transcription factor 2 (Runx2) expression in ox-LDL-treated cells. Ox-LDL-induced VSMC calcification and Runx2 expression were both inhibited by knockdown of VPO1 using a small interfering RNA or by an NADPH oxidase inhibitor. Moreover, the knockdown of VPO1 in VSMCs suppressed the production of HOCl and the phosphorylation of AKT, ERK and P38 MAPK. Furthermore, HOCl treatment facilitated the phosphorylation of AKT, ERK1/2 and P38 MAPK and the expression of Runx2, whereas LY294002 (a specific inhibitor of PI3K), U0126 (a specific inhibitor of ERK1/2) and SB203580 (a specific inhibitor of P38 MAPK) significantly attenuated the HOCl-induced up-regulation of Runx2. Collectively, these results demonstrated that VPO1 promotes ox-LDL-induced VSMC calcification via the VPO1/HOCl/PI3K/AKT, ERK1/2, and P38 MAPK/Runx2 signaling pathways. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. Athletes with higher VO2max present reduced oxLDL after a marathon race

    PubMed Central

    Bachi, André L L; Sierra, Ana Paula R; Rios, Francisco J O; Gonçalves, Danieli A; Ghorayeb, Nabil; Abud, Ronaldo L; Victorino, Angélica B; dos Santos, Juliana M B; Kiss, Maria Augusta D P; Pithon-Curi, Tania C; Vaisberg, Mauro

    2015-01-01

    Background During a session of prolonged and exhaustive exercise, such as a marathon race, large quantities of free radicals are produced and can oxidise (ox) several molecules, such as low-density lipoprotein (LDL). To prevent oxidative damage, athletes present higher antioxidant levels. However, the effect of marathon running on the natural IgM or IgG anti-oxLDL autoantibodies is not understood. Thus, we investigated the effect of a marathon race on oxidative stress and the mechanisms of control of this stress. Methods Blood samples of 20 marathon runners were collected 24 hours before, immediately and 72 hours after a marathon race to evaluate: plasma lipid profile; serum levels of oxLDL and anti-oxLDL autoantibodies (IgM and IgG isotype) and total antioxidant capacity (TAC). Maximum oxygen uptake (VO2max) was also determined. Results Immediately after the race, oxLDL and TAC levels decreased in comparison to the basal levels; however, the IgM or IgG anti-oxLDL levels remain unchanged. Whereas no differences were observed in the IgM or IgG anti-oxLDL levels 72h after the marathon, the oxLDL and TAC levels returned to the basal values. Significant positive correlations were observed between oxLDL and LDL-cholesterol before, and 72h after the marathon. Significant negative correlations were observed between oxLDL and VO2max immediately after the marathon and 72 h later, as well as between oxLDL and TAC 72 h after the race. Conclusions Athletes with a higher VO2max and total antioxidant activity presented reduced LDL oxidation. The levels of IgM or IgG anti-oxLDL autoantibodies were not affected by running the marathon. PMID:27900109

  12. Upregulation of macrophage-specific functions by oxidized LDL: lysosomal degradation-dependent and -independent pathways.

    PubMed

    Radhika, A; Sudhakaran, P R

    2013-01-01

    Formation of foam cells from macrophages, which are formed by the differentiation of blood-borne monocytes, is a critical early event in atherogenesis. To examine how pre-exposure of monocytes to modified proteins, such as oxLDL, influences their differentiation to macrophages, an in vitro model system using isolated PBMC maintained in culture in the presence of oxLDL was used. Pretreatment of monocytes with oxLDL caused a faster rate of expression of macrophage-specific functions and loss of monocyte-specific functions compared to unmodified LDL. The effect of oxidation of lipid component of LDL by CuSO(4) and its protein component by HOCl, on mo-mϕ differentiation was studied by monitoring the upregulation of macrophage-specific functions, particularly MMP-9. Chloroquine, a lysosomal degradation blocker, significantly reversed the effect mediated by CuSO(4) oxLDL, indicating the involvement of lysosomal degradation products, while no such effect was observed in HOCl oxLDL-treated cells, indicating the existence of a pathway independent of its lysosomal degradation products. Reversal of the effect of oxLDL by NAC and Calphostin C, an inhibitor of PKC, suggested the activation of RO-mediated signaling pathways. Use of inhibitors of signaling pathways showed that CuSO(4) oxLDL upregulated mϕ-specific MMP-9 through p38 MAPK and Akt-dependent pathways, while HOCl oxLDL utilized ERK ½ and Akt. Further analysis showed the activation of PPARγ and AP-1 in CuSO(4) oxLDL, while HOCl-oxLDL-mediated effect involved NFκB and AP-1. These results suggest that lipid oxLDL- and protein oxLDL-mediated upregulation of mo-mϕ-specific functions involve lysosomal degradation-dependent and -independent activation of intracellular signaling pathways.

  13. Pathogenic role of modified LDL antibodies and immune complexes in atherosclerosis.

    PubMed

    Lopes-Virella, Maria F; Virella, Gabriel

    2013-01-01

    There is strong evidence supporting a key role of the adaptive immune response in atherosclerosis, given that both activated Th cells producing predominantly interferon-γ and oxidized LDL (oxLDL) and the corresponding antibodies have been isolated from atheromatous plaques. Studies carried out using immune complexes (IC) prepared with human LDL and rabbit antibodies have demonstrated proatherogenic and pro-inflammatory properties, mostly dependent on the engagement of Fcγ receptors Ⅰ and Ⅱ in macrophages and macrophage-like cell lines. Following the development of a methodology for isolating modified LDL (mLDL) antibodies from serum and isolated IC, it was confirmed that antibodies reacting with oxLDL and advanced glycation end product-modified LDL are predominantly IgG of subtypes 1 and 3 and that mLDL IC prepared with human reagents possesses pro-inflammatory and proatherogenic properties. In previous studies, LDL separated from isolated IC has been analyzed for its modifications, and the reactivity of antibodies isolated from the same IC with different LDL modifications has been tested. Recently, we obtained strong evidence suggesting that the effects of mLDL IC on phagocytic cells are modulated by the composition of the mLDL. Clinical studies have shown that the level of mLDL in circulating IC is a strong predictor of cardiovascular disease (CVD) and, in diabetic patients, other significant complications, such as nephropathy and retinopathy. In conclusion, there is convincing ex vivo and clinical data supporting the hypothesis that, in humans, the humoral immune response to mLDL is pathogenic rather than protective.

  14. Antisense oligonucleotide reduction of apoB-ameliorated atherosclerosis in LDL receptor-deficient mice[S

    PubMed Central

    Mullick, Adam E.; Fu, Wuxia; Graham, Mark J.; Lee, Richard G.; Witchell, Donna; Bell, Thomas A.; Whipple, Charles P.; Crooke, Rosanne M.

    2011-01-01

    Chronic elevations of plasma apolipoprotein B (apoB) are strongly associated with cardiovascular disease. We have previously demonstrated that inhibition of hepatic apoB mRNA using antisense oligonucleotides (ASO) results in reductions of apoB, VLDL, and LDL in several preclinical animal models and humans. In this study, we evaluated the anti-atherogenic effects of a murine-specific apoB ASO (ISIS 147764) in hypercholesterolemic LDLr deficient (LDLr−/−) mice. ISIS 147764 was administered weekly at 25-100 mg/kg for 10-12 weeks and produced dose-dependent reductions of hepatic apoB mRNA and plasma LDL by 60-90%. No effects on these parameters were seen in mice receiving control ASOs. ApoB ASO treatment also produced dose-dependent reductions of aortic en face and sinus atherosclerosis from 50-90%, with high-dose treatment displaying less disease than the saline-treated, chow-fed LDLr−/− mice. No changes in intestinal cholesterol absorption were seen with apoB ASO treatment, suggesting that the cholesterol-lowering pharmacology of 147764 was primarily due to inhibition of hepatic apoB synthesis and secretion. In summary, ASO-mediated suppression of apoB mRNA expression profoundly reduced plasma lipids and atherogenesis in LDLr−/− mice, leading to the hypothesis that apoB inhibition in humans with impaired LDLr activity may produce similar effects. PMID:21343632

  15. Effect of dietary fat saturation and cholesterol on LDL composition and metabolism. In vivo studies of receptor and nonreceptor-mediated catabolism of LDL in cebus monkeys.

    PubMed

    Nicolosi, R J; Stucchi, A F; Kowala, M C; Hennessy, L K; Hegsted, D M; Schaefer, E J

    1990-01-01

    The mechanism(s) by which polyunsaturated fats reduce low density lipoprotein (LDL) cholesterol and apolipoprotein (apo) B were investigated in 20 cebus monkeys (Cebus albifrons) fed diets containing corn oil or coconut oil as fat (31% of calories) with or without dietary cholesterol (0.1% by weight) for 3 to 10 years. Coconut-oil feeding compared to corn-oil feeding resulted in significant increases in levels of plasma total cholesterol (176%), very low density lipoprotein (VLDL)-LDL cholesterol (236%), high density lipoprotein (HDL) cholesterol (148%), apo B (78%), and apo A-I (112%). The addition of dietary cholesterol to corn oil compared to corn oil alone resulted in smaller, but significant, increases in levels of total cholesterol (44%), HDL cholesterol (40%), and apo A-I (33%). Although the increases in VLDL-LDL cholesterol were of similar magnitude (52%), they barely failed to reach statistical significance (p less than 0.08), while the changes in apo B levels were negligible. The addition of dietary cholesterol to coconut oil, compared to coconut oil alone, resulted in no significant changes in lipoprotein cholesterol or apoproteins, although levels of VLDL-LDL cholesterol and apo B values increased 22% and 16%, respectively. Although hepatic free cholesterol content was not altered by diet, coconut-oil compared to corn-oil feeding resulted in significant increases in hepatic cholesteryl esters (236%) and triglycerides (325%), the latter increasing still further when dietary cholesterol was added to coconut oil (563%). To further assess the effects of these dietary changes on LDL metabolism, radioiodinated normal and glucosylated LDL kinetics were performed. The production rate of LDL apo B was not altered by diet. With corn-oil feeding, 63% of LDL catabolism was via the receptor-mediated pathway. Coconut-oil compared to corn-oil feeding resulted in a 50% decrease in receptor-mediated LDL apo B fractional catabolic rate (FCR) and a 27% reduction in

  16. P2Y(2)R activation by nucleotides released from oxLDL-treated endothelial cells (ECs) mediates the interaction between ECs and immune cells through RAGE expression and reactive oxygen species production.

    PubMed

    Eun, So Young; Park, Sang Won; Lee, Jae Heun; Chang, Ki Churl; Kim, Hye Jung

    2014-04-01

    Lipoprotein oxidation, inflammation, and immune responses involving the vascular endothelium and immune cells contribute to the pathogenesis of atherosclerosis. In an atherosclerotic animal model, P2Y2 receptor (P2Y2R) upregulation and stimulation were previously shown to induce intimal hyperplasia and increased intimal monocyte infiltration. Thus, we investigated the role of P2Y2R in oxidized low-density lipoprotein (oxLDL)-mediated oxidative stress and the subsequent interaction between endothelial cells (ECs) and immune cells. The treatment of human ECs with oxLDL caused the rapid release of ATP (maximum after 5 min). ECs treated with oxLDL or the P2Y2R agonists ATP/UTP for 1h exhibited significant reactive oxygen species (ROS) production, but this effect was not observed in P2Y2R siRNA-transfected ECs. In addition, oxLDL and ATP/UTP both induced RAGE expression, which was P2Y2R dependent. Oxidized LDL- and ATP/UTP-mediated ROS production was diminished in RAGE siRNA-transfected ECs, suggesting that RAGE is an important mediator in P2Y2R-mediated ROS production. Treatment with oxLDL for 24h induced P2Y2R expression in the human monocyte cell line THP-1 and increased THP-1 cell migration toward ECs. The addition of apyrase, an enzyme that hydrolyzes nucleotides, or diphenyleneiodonium (DPI), a well-known inhibitor of NADPH oxidase, significantly inhibited the increase in cell migration caused by oxLDL. P2Y2R siRNA-transfected THP-1 cells did not migrate in response to oxLDL or ATP/UTP treatment, indicating a critical role for P2Y2R and nucleotide release in oxLDL-induced monocyte migration. Last, oxLDL and ATP/UTP effectively increased ICAM-1 and VCAM-1 expression and the subsequent binding of THP-1 cells to ECs, which was inhibited by pretreatment with DPI or by siRNA against P2Y2R or RAGE, suggesting that P2Y2R is an important mediator in oxLDL-mediated monocyte adhesion to ECs through the regulation of ROS-dependent adhesion molecule expression in ECs. Taken

  17. Effects of lowering LDL cholesterol on progression of kidney disease.

    PubMed

    Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Agodoa, Lawrence; Cass, Alan; Craig, Jonathan C; de Zeeuw, Dick; Feldt-Rasmussen, Bo; Fellström, Bengt; Levin, Adeera; Wheeler, David C; Walker, Rob; Herrington, William G; Baigent, Colin; Landray, Martin J

    2014-08-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. Copyright © 2014 by the American Society of Nephrology.

  18. Effects of Lowering LDL Cholesterol on Progression of Kidney Disease

    PubMed Central

    Haynes, Richard; Lewis, David; Emberson, Jonathan; Reith, Christina; Agodoa, Lawrence; Cass, Alan; Craig, Jonathan C.; de Zeeuw, Dick; Feldt-Rasmussen, Bo; Fellström, Bengt; Levin, Adeera; Wheeler, David C.; Walker, Rob; Herrington, William G.; Baigent, Colin; Landray, Martin J.; Baigent, Colin; Landray, Martin J.; Reith, Christina; Emberson, Jonathan; Wheeler, David C.; Tomson, Charles; Wanner, Christoph; Krane, Vera; Cass, Alan; Craig, Jonathan; Neal, Bruce; Jiang, Lixin; Hooi, Lai Seong; Levin, Adeera; Agodoa, Lawrence; Gaziano, Mike; Kasiske, Bertram; Walker, Rob; Massy, Ziad A.; Feldt-Rasmussen, Bo; Krairittichai, Udom; Ophascharoensuk, Vuddidhej; Fellström, Bengt; Holdaas, Hallvard; Tesar, Vladimir; Wiecek, Andrzej; Grobbee, Diederick; de Zeeuw, Dick; Grönhagen-Riska, Carola; Dasgupta, Tanaji; Lewis, David; Herrington, Will; Mafham, Marion; Majoni, William; Wallendszus, Karl; Grimm, Richard; Pedersen, Terje; Tobert, Jonathan; Armitage, Jane; Baxter, Alex; Bray, Christopher; Chen, Yiping; Chen, Zhengming; Hill, Michael; Knott, Carol; Parish, Sarah; Simpson, David; Sleight, Peter; Young, Alan; Collins, Rory

    2014-01-01

    Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecified tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. PMID:24790178

  19. Estimation of LDL Particle Size Using Lipid Indices: A Population-Based Study of 1578 Schoolchildren.

    PubMed

    Watabe, Yaeko; Arisaka, Osamu; Miyake, Noriko; Ichikawa, Go; Koyama, Satomi; Shimura, Naoto

    2015-12-01

    Low-density lipoprotein (LDL) is atherogenic and LDL particles are reduced in diameter in the presence of insulin resistance, forming small, dense LDL. This study was conducted to assess the relationship between commonly used lipid indices and LDL particle size and furthermore to clarify the best surrogate lipid markers that could conveniently be used to estimate LDL particle size in children. We determined LDL particle diameter by gradient gel electrophoresis in 1578 children aged 10-12 years. At the fasting state, the relationships between measured LDL particle size and lipid variables [total cholesterol (TC), triglycerides (TG), LDL-cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), atherogenic index [(TC-HDL-C)/HDL-C, TG/HDL-C, LDL-C/HDL-C, and LDL-C/apolipoprotein B (Apo B) and non-HDL-C (TC-HDL-C)] were analyzed. The LDL particle diameter was 26.64 (mean) ± 0.48 (SD) nm in boys (n = 820) and 26.66 ± 0.49 nm in girls (n = 758); there was not a statistically significant difference. There were statistically significant correlations between LDL particle size and TG or HDL-C concentrations (r = 0.28∼0.37), but the correlations with LDL-C and ApoB were very weak. The combined lipid measures, such as atherogenic index, TC/HDL-C, TG/HDL-C, and LDL-C/HDL-C showed moderate correlations (r = 0.33∼0.38) with LDL particle size; however, the correlation of non-HDL-C with LDL particle size was weak (r = 0.18∼0.19). Simple HDL-C measure appeared to be of comparable value to combined lipid measures. Our data indicate that various lipid indices are not superior to HDL-C levels alone as a clinical tool for estimating LDL particle size. Non-HDL-C was less valuable in this aspect.

  20. Effects of dietary saturated fat on LDL subclasses and apolipoprotein CIII in men.

    PubMed

    Faghihnia, N; Mangravite, L M; Chiu, S; Bergeron, N; Krauss, R M

    2012-11-01

    Small dense low-density lipoprotein (LDL) particles and apolipoprotein (apo) CIII are risk factors for cardiovascular disease (CVD) that can be modulated by diet, but there is little information regarding the effects of dietary saturated fat on their plasma levels. We tested the effects of high vs low saturated fat intake in the context of a high beef protein diet on levels and composition of LDL subclasses and on apoCIII levels in plasma and LDL. Following consumption of a baseline diet (50% carbohydrate (CHO), 13% protein, 38% total fat, 15% saturated fat) for 3 weeks, 14 healthy men were randomly assigned to two reduced CHO high beef protein diets (31% CHO, 31% protein, 38% fat) that differed in saturated fat content (15% vs 8%) for 3 weeks each in a crossover design. The high saturated fat (HSF) diet resulted in higher mass concentrations of buoyant LDL I, medium density LDL II and dense LDL III, but not the very dense LDL IV; and significant increases in plasma and LDL apoCIII concentration of 9.4% and 33.5%, respectively. The saturated fat-induced changes in LDL apoCIII were specifically correlated with changes in apoCIII content of LDL IV. Taken together with previous observations, these findings suggest that, at least in the context of a lower CHO high beef protein diet, HSF intake may increase CVD risk by metabolic processes that involve apoCIII.

  1. The Mediterranean Diet decreases LDL atherogenicity in high cardiovascular risk individuals: a randomized controlled trial.

    PubMed

    Hernáez, Álvaro; Castañer, Olga; Goday, Alberto; Ros, Emilio; Pintó, Xavier; Estruch, Ramón; Salas-Salvadó, Jordi; Corella, Dolores; Arós, Fernando; Serra-Majem, Lluis; Martínez-González, Miguel Ángel; Fiol, Miquel; Lapetra, José; de la Torre, Rafael; López-Sabater, M Carmen; Fitó, Montserrat

    2017-09-01

    Traditional Mediterranean diet (TMD) protects against cardiovascular disease through several mechanisms such as decreasing LDL cholesterol levels. However, evidence regarding TMD effects on LDL atherogenic traits (resistance against oxidation, size, composition, cytotoxicity) is scarce. We assessed the effects of a 1-year intervention with a TMD on LDL atherogenic traits in a random sub-sample of individuals from the PREDIMED study (N = 210). We compared two TMDs: one enriched with virgin olive oil (TMD-VOO, N = 71) and another with nuts (TMD-Nuts, N = 68), versus a low-fat control diet (N = 71). After the TMD-VOO intervention, LDL resistance against oxidation increased (+6.46%, p = 0.007), the degree of LDL oxidative modifications decreased (-36.3%, p<0.05), estimated LDL particle size augmented (+3.06%, p = 0.021), and LDL particles became cholesterol-rich (+2.41% p = 0.013) relative to the low-fat control diet. LDL lipoproteins became less cytotoxic for macrophages only relative to baseline (-13.4%, p = 0.019). No significant effects of the TMD-Nuts intervention on LDL traits were observed versus the control diet. Adherence to a TMD, particularly when enriched with virgin olive oil, decreased LDL atherogenicity in high cardiovascular risk individuals. The development of less atherogenic LDLs could contribute to explaining some of the cardioprotective benefits of this dietary pattern. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Cross-reactive saliva IgA antibodies to oxidized LDL and periodontal pathogens in humans.

    PubMed

    Akhi, Ramin; Wang, Chunguang; Kyrklund, Mikael; Kummu, Outi; Turunen, Sini Pauliina; Hyvärinen, Kati; Kullaa, Arja; Salo, Tuula; Pussinen, Pirkko J; Hörkkö, Sohvi

    2017-07-01

    Oxidized low-density lipoproteins (oxLDL) are formed as a result of lipid peroxidation and are highly immunogenic and proatherogenic. In this study, saliva antibodies binding to oxLDL, Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa) were characterized and their cross-reactivity was evaluated. Resting and stimulated saliva samples were collected from 36 healthy adults (mean age 26 years). Saliva IgA, IgG and IgM autoantibody levels to copper oxidized LDL (CuOx-LDL) and malondialdehyde acetaldehyde-modified LDL (MAA-LDL) were determined with chemiluminescence immunoassay. Saliva IgA and IgG antibodies binding to MAA-LDL and CuOx-LDL were detected in all samples and they were associated with the saliva levels of IgA and IgG to P. gingivalis and A. actinomycetemcomitans. Competitive immunoassay showed that saliva antibodies to MAA-LDL cross-reacted specifically with P. gingivalis. The autoantibody levels to oxLDL in saliva were not associated with the autoantibody levels to oxLDL in plasma or with saliva apolipoprotein B 100 levels. Saliva contains IgA and IgG binding to oxLDL, which showed cross-reactive properties with the periodontal pathogens Porphyromonas gingivalis (P.g). The data suggest that secretory IgA to P.g may participate in immune reactions involved in LDL oxidation through molecular mimicry. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Ordovas-Oxidized LDL is associated with metabolic syndrome traits independently of central obesity and insulin resistance

    USDA-ARS?s Scientific Manuscript database

    This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baselin...

  4. Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis.

    PubMed

    Lu, Mengxiao; Gantz, Donald L; Herscovitz, Haya; Gursky, Olga

    2012-10-01

    Fusion of modified LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the first quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, E(a) = 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negative-stain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the first kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase the particle size may have opposite effects on LDL fusion.

  5. Kinetic analysis of thermal stability of human low density lipoproteins: a model for LDL fusion in atherogenesis[S

    PubMed Central

    Lu, Mengxiao; Gantz, Donald L.; Herscovitz, Haya; Gursky, Olga

    2012-01-01

    Fusion of modified LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the first quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, Ea = 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negative-stain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the first kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase the particle size may have opposite effects on LDL fusion. PMID:22855737

  6. Annexin A2 is a natural extrahepatic inhibitor of the PCSK9-induced LDL receptor degradation.

    PubMed

    Seidah, Nabil G; Poirier, Steve; Denis, Maxime; Parker, Rex; Miao, Bowman; Mapelli, Claudio; Prat, Annik; Wassef, Hanny; Davignon, Jean; Hajjar, Katherine A; Mayer, Gaétan

    2012-01-01

    Proprotein convertase subtilisin/kexin-9 (PCSK9) enhances the degradation of hepatic low-density lipoprotein receptor (LDLR). Deletion of PCSK9, and loss-of-function mutants in humans result in lower levels of circulating LDL-cholesterol and a strong protection against coronary heart disease. Accordingly, the quest for PCSK9 inhibitors has major clinical implications. We have previously identified annexin A2 (AnxA2) as an endogenous binding partner and functional inhibitor of PCSK9. Herein, we studied the relevance of AnxA2 in PCSK9 inhibition and lipid metabolism in vivo. Plasma analyses of AnxA2(-/-) mice revealed: i) a ∼1.4-fold increase in LDL-cholesterol without significant changes in VLDLs or HDLs, and ii) a ∼2-fold increase in circulating PCSK9 levels. Western blotting and immunohistochemistry of AnxA2(-/-) tissues revealed that the LDLR was decreased by ∼50% in extrahepatic tissues, such as adrenals and colon. We also show that AnxA2-derived synthetic peptides block the PCSK9≡LDLR interaction in vitro, and adenoviral overexpression of AnxA2 in mouse liver increases LDLR protein levels in vivo. These results suggest that AnxA2 acts as an endogenous regulator of LDLR degradation, mostly in extrahepatic tissues. Finally, we identified an AnxA2 coding polymorphism, V98L, that correlates with lower circulating levels of PCSK9 thereby extending our results on the physiological role of AnxA2 in humans.

  7. Oats (Avena sativa) reduce atherogenesis in LDL-receptor-deficient mice.

    PubMed

    Andersson, K E; Svedberg, K A; Lindholm, M W; Oste, R; Hellstrand, P

    2010-09-01

    The cholesterol-lowering properties of oats, largely ascribed to its contents of soluble fibers, beta-glucans, are well established, whereas effects on atherogenesis are less well elucidated. Oats also contains components with reported antioxidant and anti-inflammatory effects that may affect atherogenesis. In this work we examined effects of oat bran on plasma cholesterol, markers of inflammation, eNOS expression and development of atherosclerosis in LDL-receptor-deficient (LDLr(-/-)) mice. Female LDLr(-/-) mice were fed Western diet+/-oat bran. Two concentrations of oat bran (40 and 27%) were compared regarding effects on plasma lipids. There was a dose-dependent reduction of plasma cholesterol by 42 and 20% with 40 and 27% oat bran, respectively. Both concentrations also lowered plasma triglycerides (by 45 and 33%) and relative levels of plasma LDL+VLDL. The reduction of plasma lipids was accompanied by increased faecal excretion of cholesterol and bile acids. Oat bran (40%) efficiently reduced atherosclerotic lesion area in the descending aorta (-77%) and aortic root (-33%). Plasma levels of fibrinogen and soluble vascular cell adhesion molecule-1 (VCAM-1) were significantly lower, and immunofluorescence of aortic sections revealed a 75% lower expression of VCAM-1 in oat-fed mice. The expression of eNOS protein in the aortic wall was increased in mice fed oat bran. Oat bran supplemented to a Western diet lowers plasma cholesterol, reduces levels of some inflammatory markers, increases eNOS expression and inhibits atherosclerotic lesion development in LDLr(-/-) mice. It remains to be investigated which components in oats contribute to these effects. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

  8. Magnesium fortification of drinking water suppresses atherogenesis in male LDL-receptor-deficient mice.

    PubMed

    Sherer, Y; Shaish, A; Levkovitz, H; Keren, P; Janackovic, Z; Shoenfeld, Y; Harats, D

    1999-01-01

    Magnesium, an important cofactor of more than 300 enzymes, has previously been found to modulate blood lipid levels, atherogenesis and atherosclerosis in rabbits, when added to their diet. The aim of this study was to examine whether magnesium fortification of drinking water, without a change in diet content, can affect atherogenesis. The study included six groups of LDL-receptor-deficient mice. The mice received either distilled water or water containing 50 g of magnesium sulfate per liter. In the first (12 weeks) and second (6 weeks) stages of the experiment, the mice received low- and high-cholesterol diets, respectively. At the end of each stage, blood was drawn for the determination of plasma magnesium, calcium and lipid levels. In addition, the extent of atherosclerosis was determined at the aortic sinus. In both males and females, magnesium fortification was associated with higher levels of plasma magnesium (50 and 37% increase, respectively), without any differences in plasma calcium content. The extent of atherosclerosis at the aortic sinus in the male mice that received high levels of magnesium was a third of that of the male mice that received distilled water. However, these differences were not found in the female groups. Surprisingly, the female mice that received water fortified with magnesium had higher levels of cholesterol after stage 2, whereas no differences regarding plasma lipid levels were found among the male mice. These results confirm that magnesium fortification of drinking water is capable of inhibiting atherogenesis in male LDL-receptor-deficient mice. The mechanisms of action are yet to be discovered, and are probably not related to diminished lipid excretion, but possibly to the prevention of calcium influx into vascular smooth muscle cells, elevated antioxidative capacity, or other yet undetermined mechanisms.

  9. Blockade of Tim-1 and Tim-4 Enhances Atherosclerosis in LDL Receptor-Deficient Mice

    PubMed Central

    Foks, Amanda C.; Engelbertsen, Daniel; Kuperwaser, Felicia; Alberts-Grill, Noah; Gonen, Ayelet; Witztum, Joseph L.; Lederer, James; Jarolim, Petr; DeKruyff, Rosemarie H.; Freeman, Gordon J.; Lichtman, Andrew H.

    2016-01-01

    Objective T cell immunoglobulin and mucin domain (Tim) proteins are expressed by numerous immune cells, recognize phosphatidylserine (PS) on apoptotic cells and function as costimulators or coinhibitors. Tim-1 is expressed by activated T cells but is also found on dendritic cells and B cells. Tim-4, present on macrophages and dendritic cells, plays a critical role in apoptotic cell clearance, regulates the number of PS-expressing activated T cells and is genetically associated with low LDL and triglyceride levels. Since these functions of Tim-1 and Tim-4 could affect atherosclerosis, their modulation has potential therapeutic value in cardiovascular disease. Approach and Results ldlr−/− mice were fed a high-fat diet for 4 weeks while being treated with control (rat IgG1) or anti-Tim-1 (3D10) or -Tim-4 (21H12) mAbs that block PS recognition and phagocytosis. Both anti-Tim-1 and anti-Tim-4 treatments enhance atherosclerosis by 45% compared with controls by impairment of efferocytosis and increasing aortic CD4+T cells. Consistently, anti-Tim-4-treated mice show increased percentages of activated T cells and 'late' apoptotic cells in the circulation. Moreover, in vitro blockade of Tim-4 inhibited efferocytosis of oxLDL-induced apoptotic macrophages. Whereas anti-Tim-4 treatment increased Th1 and Th2 responses, anti-Tim-1 induced Th2 responses but dramatically reduced the percentage of Tregs. Finally, combined blockade of Tim-1 and Tim-4 increased atherosclerotic lesion size by 59%. Conclusion Blockade of Tim-4 aggravates atherosclerosis likely by prevention of phagocytosis of PS-expressing apoptotic cells and activated T cells by Tim-4-expressing cells, whereas Tim-1-associated effects on atherosclerosis are related to changes in Th1/Th2 balance and reduced circulating Tregs. PMID:26821944

  10. Symmetry breaking in the planar configurations of disilicon tetrahalides: Pseudo-Jahn-Teller effect parameters, hardness and electronegativity.

    PubMed

    Kouchakzadeh, Ghazaleh; Nori-Shargh, Davood

    2015-11-21

    CCSD(T), MP2, LC-BLYP, LC-ωPBE and B3LYP methods with the Def2-TZVPP basis set and natural bond orbital (NBO) interpretations were performed to investigate the correlations between the Pseudo-Jahn-Teller Effect (PJTE) parameters [i.e. vibronic coupling constant values (F), energy gaps between reference states (Δ) and the primary force constant (K0)], structural and configurational properties, global hardness, global electronegativity, natural bond orders, stabilization energies associated with electron delocalizations and natural atomic charges of disilicon tetrafluoride (1), disilicon tetrachloride (2), disilicon tetrabromide (3) and disilicon tetraiodide (4). All levels of theory showed the trans-bent (C2h) configurations as the energy minimum structures of compounds 1-4, and the flap angles between the X2Si planes and the Si=Si bonds in the distorted (C2h) configurations decrease from compound 1 to compound 4. The negative curvatures of the ground state electronic configurations and the positive curvatures of the excited states of the adiabatic potential energy surfaces (APESs) which resulted from the mixing of the ground Ag and excited B2g states are due to the PJTE (i.e. PJT(Ag + B2g) ⊗ b2g problem). Contrary to the usual expectation, with the decrease of the energy gaps between reference states (Δ), the PJTE stabilization energy, E(PJT), decreases from compound 1 to compound 4. The canonical molecular orbital (CMO) analysis revealed that the contributions of the ψ(HOMO)(b3u) and ψL(UMO)(b1u) molecular orbitals in the vibronic coupling constant (F) decrease from compound 1 to compound 4. This fact clearly justifies the decrease of the vibronic coupling constant (F) and the primary force constant (the force constant without the PJTE) values on going from compound 1 to compound 4, leading to the decrease of the negative curvatures of the ground state electronic configuration curves of their corresponding APESs. The results obtained showed that the

  11. Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro

    PubMed Central

    Menéndez, Roberto; Más, Rosa; Amor, Ana MA; González, Rosa MA; Fernández, Julio C; Rodeiro, Idania; Zayas, Mirta; Jiménez, Sonia

    2000-01-01

    Aims The aim of this study was to investigate the effect of policosanol on the susceptibility of LDL-C to in vitro lipid peroxidation in human healthy volunteers. Methods The effect of policosanol (5 and 10 mg day−1) on LDL-C oxidation was studied in a double-blind, randomized, placebo-controlled trial conducted in 69 subjects. LDL-C samples isolated at baseline and after 8 weeks were subjected to in vitro tests of LDL-C oxidation. We tested the susceptibility of LDL-C to lipid peroxidation in a cell-free system by the addition of copper ions as well as in a more physiological system, macrophage-mediated oxidation. Results At baseline all groups were well matched regarding all variables. After 8 weeks of therapy policosanol administered at 5 and 10 mg, significantly and in a dose-dependent manner increased the lag phase of conjugated diene generation (mean ± s.d.) from 83.79 ± 29.16 min to 94.90 ± 25.50 min (5 mg day−1) and from 82.74 ± 17.16 min to 129.89 ± 35.71 min (10 mg day−1), while in the placebo group LDL-C oxidation did not change significantly. Policosanol (10 mg day−1), but not placebo, significantly decreased the rate of conjugated diene generation. Comparison with placebo after therapy also showed significant differences. Macrophage mediated-oxidation was also inhibited by policosanol as evident by measuring thiobarbituric acid reactive substances (TBARS). Policosanol (10 mg day−1) significantly lowered malondialdehyde (MDA) generation from 8.50 ± 0.91 to 5.76 ± 1.01 nmol mg−1 protein. Comparison with placebo after 5 and 10 mg day−1 showed significant differences. Policosanol significantly lowered total cholesterol by 10.5% (5 mg day−1) and 12.4% (10 mg day−1) and LDL-C by 16.7% and 20.2%, respectively. Also, policosanol (10 mg day−1) increased HDL-C by 15.2%. Five subjects withdrew from the study, none because of adverse experiences. No clinical or blood biochemical drug-related disturbances were found. Conclusions The

  12. Comparison of an oleic acid enriched-diet vs NCEP-I diet on LDL susceptibility to oxidative modifications.

    PubMed

    Castro, P; Miranda, J L; Gómez, P; Escalante, D M; Segura, F L; Martín, A; Fuentes, F; Blanco, A; Ordovás, J M; Jiménez, F P

    2000-01-01

    The objective of this trial was to compare the effect on the susceptibility of plasma Low Density Lipoprotein (LDL) to oxidative modifications of consumption of two oleic rich diets, prepared with two different plant oils, virgin olive oil (OL)1 and refined high monounsaturated fatty acids (MUFA sunflower oil (SU)), with the susceptibility of plasma LDL to oxidation after an National Cholesterol Education Program step 1 (NCEP-I) phase diet. A randomized crossover design. Twenty-two healthy normolipidemic young males consumed an NCEP-I diet for a 4-week period. Subjects were then assigned to two diets each of 4-weeks duration. Group one was placed on an olive oil enriched diet (40% fat, 22% MUFA) followed by a 4-week period of a MUFA diet enriched in sunflower oil (40% fat, 22% MUFA). In group two, the order of the diets was reversed. Both MUFA diets induced a decrease in saturated (14:0, 16:0, and 18:0) and an increase in monounsaturated and polyunsaturated n-6 (18:2, 20:3, and 20:5) plasma LDL-phospholipid fatty acids, compared to the NCEP-I diet (P<0.01). No significant differences in lag times were observed between the olive oil and the NCEP-I diet periods. However there was a greater inhibition time (P<0.001) when subjects consumed the MUFA rich sunflower oil diet compared to the NCEP-I diet. These differences were probably related to the relative enrichment of plasma LDL particles in alpha-tocopherol due to the high vitamin E content of the MUFA-rich sunflower oil. Indeed, the alpha-tocopherol content was positively correlated with lag time (r=0.338; P<0.008). Our findings suggest that changes in plasma LDL alpha-tocopherol content with practical solid-food diets can decrease its susceptibility to oxidation. This work has been supported by grants from the Investigaciones de la Seguridad Social (FIS 92/0182, to Francisco Pérez Jiménez); and from Koype Co, Andújar, Jaén, Spain. European Journal of Clinical Nutrition (2000) 54, 61-67

  13. An evaluation of low-dose simvastatin in achieving LDL goal: a retrospective chart review.

    PubMed

    Schnee, David M; Bogdanski, Laura; Zaiken, Kathy; McCloskey, William W

    2007-05-01

    Treatment for hyperciholesterolemia targets low-density lipoprotein (LDL) cholesterol. In July 2004, an update to the existingcholesterol guidelines was published that recommended more intense lowering of LDL levels. This study, a retrospective chart review conducted at a multispecialty medical group practice, aimed to determine iflow-dose simvastatin (5 or 10 mg) was effective at achieving LDL goal, in light of these more aggressive guidelines. Demographic data, including risk factors and LDL levels, were collected on 173 patients identified as taking low-dose simvastatin. The review indicated that 66% of patients with low-to-rnoderate cardiovascular risk treated with low-dose simvastatin achieved their risk-appropriate LDL goalMore than 50% of patients who achieved this LDL goal on low-dose simvastatin fell into lower-risk cattegories. Therefore, low-dose simvastatin may be a beneficial treatment option for patients in lower cardiovascular-risk categories.

  14. Marked hypocholesterolemia in a case with adrenal adenoma--enhanced catabolism of low density lipoprotein (LDL) via the LDL receptors of tumor cells.

    PubMed

    Nakagawa, T; Ueyama, Y; Nozaki, S; Yamashita, S; Menju, M; Funahashi, T; Kameda-Takemura, K; Kubo, M; Tokunaga, K; Tanaka, T

    1995-01-01

    A 16-yr-old girl was hospitalized because of amenorrhea and virilism, and was diagnosed with an adrenal tumor on the right side. Her serum androgen levels were markedly elevated, and severe hypocholesterolemia (total cholesterol, 0.59 mmol/L) was observed. After resection of the tumor, her serum cholesterol level dramatically rose to normal, suggesting a role of this tumor in her marked hypocholesterolemia. To investigate the mechanism of hypocholesterolemia in this case, we examined the effects of dehydroepiandrosterone and dehydroepiandrosterone sulfate on the low density lipoprotein (LDL) receptor activity of fibroblasts. These hormones did not have any effect on LDL receptor activity. Northern blot analysis demonstrated that the LDL receptor messenger ribonucleic acid level of this tumor tissue was increased about 8-fold compared with that of normal adrenal cortex. The LDL receptor activity of the cultured cells established from this tumor was 2-fold higher than that of Hep G2 cells. Furthermore, the LDL receptor activity could not be down-regulated by an excessive dose of 25-hydroxycholesterol. These results suggest that increased LDL receptor activity and unrestricted uptake of LDL by the adrenal tumor may have caused the marked hypocholesterolemia in this patient.

  15. HMGB1 Silencing Potentiates the Anti-inflammatory Effects of Sodium Ferulate in ox-LDL-Stimulated Vascular Smooth Muscle Cells.

    PubMed

    Hu, Nan; Kong, Lingshang; Qian, Aimin; Meng, Qingyou; Li, Chenglong; Yu, Xiaobin; Chen, Hong; Du, Xiaolong; Li, Xiaoqiang

    2015-05-01

    Atherosclerosis is a sustained inflammatory disease of the arterial wall. The purpose of the current study is to investigate the effect of sodium ferulate on the proliferation and migration of human vascular smooth muscle cells (hVSMCs). In addition, we also sought to determine whether HMGB1 knockdown could potentiate the anti-inflammatory effects of sodium ferulate. hVSMCs were treated with oxidized lower-density lipoprotein (ox-LDL, 50 mg/l) to induce inflammation. Cells were then treated with sodium ferulate and HMGB1 silencing (SiHMGB1) individually or in combination. The phenotypes of the treated cells including proliferation, cell cycle profile, apoptosis, and gene expression were analyzed. Results showed that sodium ferulate or SiHMGB1 treatment inhibited ox-LDL-induced inflammation in hVSMCs. Furthermore, the combination of SiHMGB1 plus sodium ferulate treatment displayed an additive effect in inhibiting the proliferation and migration of hVSMCs. Consistently, the suppression of receptor for advanced glycation end products expression was also observed. ICAM-1 and transforming growth factor-β suggest that these signaling components were involved in the anti-inflammatory effect. Our study confirms the anti-inflammatory function of sodium ferulate, and uncovered the potentiating effect of HMGB1 knockdown in suppressing ox-LDL-induced proliferation and migration of hVSMCs. Inhibition of HMGB1 expression in addition to sodium ferulate treatment might be a more effective therapeutic approach for atherosclerosis.

  16. The IDOL–UBE2D complex mediates sterol-dependent degradation of the LDL receptor

    PubMed Central

    Zhang, Li; Fairall, Louise; Goult, Benjamin T.; Calkin, Anna C.; Hong, Cynthia; Millard, Christopher J.; Tontonoz, Peter; Schwabe, John W.R.

    2011-01-01

    We previously identified the E3 ubiquitin ligase IDOL as a sterol-dependent regulator of the LDL receptor (LDLR). The molecular pathway underlying IDOL action, however, remains to be determined. Here we report the identification and biochemical and structural characterization of an E2–E3 ubiquitin ligase complex for LDLR degradation. We identified the UBE2D family (UBE2D1–4) as E2 partners for IDOL that support both autoubiquitination and IDOL-dependent ubiquitination of the LDLR in a cell-free system. NMR chemical shift mapping and a 2.1 Å crystal structure of the IDOL RING domain–UBE2D1 complex revealed key interactions between the dimeric IDOL protein and the E2 enzyme. Analysis of the IDOL–UBE2D1 interface also defined the stereochemical basis for the selectivity of IDOL for UBE2Ds over other E2 ligases. Structure-based mutations that inhibit IDOL dimerization or IDOL–UBE2D interaction block IDOL-dependent LDLR ubiquitination and degradation. Furthermore, expression of a dominant-negative UBE2D enzyme inhibits the ability of IDOL to degrade the LDLR in cells. These results identify the IDOL–UBE2D complex as an important determinant of LDLR activity, and provide insight into molecular mechanisms underlying the regulation of cholesterol uptake. PMID:21685362

  17. Synergistic enhancement of cytokine-induced human monocyte matrix metalloproteinase-1 by C-reactive protein and oxidized LDL through differential regulation of monocyte chemotactic protein-1 and prostaglandin E2.

    PubMed

    Zhang, Yahong; Wahl, Larry M

    2006-01-01

    C-reactive protein (CRP) and oxidized LDL (ox-LDL) are associated with inflammatory lesions, such as coronary artery disease, in which monocytes and matrix metalloproteinases (MMPs) may play a major role in the rupture of atherosclerotic plaques. Monocytes are recruited to inflammation sites by monocyte chemoattractant protein-1 (MCP-1), which may also participate in the activation of monocytes. The objective of this study was to compare the individual and combined effect of CRP and ox-LDL on human monocyte MMP-1 and the role of MCP-1 in this effect. Although CRP or ox-LDL failed to induce MMP-1 in control monocytes, these molecules enhanced MMP-1 production induced by tumor necrosis factor alpha (TNF-alpha) and granulocyte macrophage-colony stimulating factor (GM-CSF) with a synergistic increase in MMP-1 occurring in the presence of both mediators. Enhancement of MMP-1 by CRP and ox-LDL was attributable to a differential increase in MCP-1 and prostaglandin E2(PGE2). CRP, at physiological concentrations, induced high levels of MCP-1 and relatively low levels of PGE2, whereas ox-LDL caused a significant enhancement of PGE2 with little affect on MCP-1. Accordingly, CRP- and ox-LDL-induced MMP-1 production by monocytes was inhibited by anti-MCP-1 antibodies and indomethacin, respectively. Moreover, addition of exogenous MCP-1 or PGE2 enhanced MMP-1 production by TNF-alpha- and GM-CSF-stimulated monocytes. These results show that the combination of CRP and ox-LDL can cause a synergistic enhancement of the role of monocytes in inflammation, first, by increasing MCP-1, which attracts more monocytes and directly enhances MMP-1 production by activated monocytes, and second, by elevating PGE2 production, which also leads to higher levels of MMP-1.

  18. A high LDL-C to HDL-C ratio predicts poor prognosis for initially metastatic colorectal cancer patients with elevations in LDL-C.

    PubMed

    Liao, Fangxin; He, Wenzhuo; Jiang, Chang; Yin, Chenxi; Guo, Guifang; Chen, Xuxian; Qiu, Huijuan; Rong, Yuming; Zhang, Bei; Xu, Dazhi; Xia, Liangping

    2015-01-01

    Although lipid disequilibrium has been documented for several types of cancer including colorectal cancer (CRC), it remains unknown whether lipid parameters are associated with the outcome of metastatic CRC (mCRC) patients. Here, we retrospectively examined the lipid profiles of 453 mCRC patients and investigated whether any of the lipid parameters correlated with the outcome of mCRC patients. Pretreatment serum lipids, including triglyceride, cholesterol, high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), were collected in 453 initially mCRC patients. The LDL-C to HDL-C ratio (LHR) was calculated and divided into the first, second, and third tertiles. Univariate and multivariate analyses were performed to evaluate the impact of lipids on overall survival (OS) and progression-free survival (PFS). Nearly two-fifths of the patients (41.3%) exhibited elevations in LDL-C while most patients (88.3%) showed normal HDL-C levels. Decreased HDL-C (P=0.542) and increased LDL-C (P=0.023) were prognostic factors for poor OS, while triglyceride (P=0.542) and cholesterol (P=0.215) were not. Multivariate analysis revealed that LDL-C (P=0.031) was an independent prognostic factor. Triglyceride, cholesterol, HDL-C, and LDL-C did not correlate with PFS. Among patients with elevations in LDL-C levels, patients in the third tertile of the LHR had a markedly shorter median OS compared to those in the first or second tertile (P=0.012). Thus, increased LDL-C level is an independent prognostic factor for poor prognosis in mCRC patients, and a high LHR predicts poor prognosis for initially mCRC patients with elevations in LDL-C.

  19. A novel posttranscriptional mechanism for dietary cholesterol-mediated suppression of liver LDL receptor expression[S

    PubMed Central

    Singh, Amar Bahadur; Kan, Chin Fung Kelvin; Shende, Vikram; Dong, Bin; Liu, Jingwen

    2014-01-01

    It is well-established that over-accumulation of dietary cholesterol in the liver inhibits sterol-regulatory element binding protein (SREBP)-mediated LDL receptor (LDLR) gene transcription leading to a reduced hepatic LDLR mRNA level in hypercholesterolemic animals. However, it is unknown whether elevated cholesterol levels can elicit a cellular response to increase LDLR mRNA turnover to further repress LDLR expression in liver tissue. In the current study, we examined the effect of a high cholesterol diet on the hepatic expression of LDLR mRNA binding proteins in three different animal models and in cultured hepatic cells. Our results demonstrate that high cholesterol feeding specifically elevates the hepatic expression of LDLR mRNA decay promoting factor heterogeneous nuclear ribonucleoprotein (HNRNP)D without affecting expressions of other LDLR mRNA binding proteins in vivo and in vitro. Employing the approach of adenovirus-mediated gene knockdown, we further show that depletion of HNRNPD in the liver results in a marked reduction of serum LDL-cholesterol and a substantial increase in liver LDLR expression in hyperlipidemic mice. Additional studies of gene knockdown in albumin-luciferase-untranslated region (UTR) transgenic mice provide strong evidence supporting the essential role of 3′UTR in HNRNPD-mediated LDLR mRNA degradation in liver tissue. Altogether, this work identifies a novel posttranscriptional regulatory mechanism by which dietary cholesterol inhibits liver LDLR expression via inducing HNRNPD to accelerate LDLR mRNA degradation. PMID:24792925

  20. Cytokeratin 8 in Association with sdLDL and ELISA Development

    PubMed Central

    Ashmaig, Mohmed

    2015-01-01

    Background: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Cytokeratins (CKs) which may also be expressed in vascular smooth muscle cells (SMCs) are generally considered to be markers for the differentiation of epithelial cells. Small, dense, low-density lipoprotein (sdLDL) particles, also termed LDL-IV, independently predict risk of CVD. Aims: The aims of this study were to develop an analytical method, apart from ultracentrifugation capable of isolating sdLDL in order to study any associated proteins. Materials and Methods: Using modified gradient gel electrophoresis (GGE), de-identified sdLDL-enriched plasma was used to physically elute and isolate sdLDL particles. To validate the finding, additional plasma from 77 normal and 48 higher risk subjects were used to measure sdLDL particles and CK8. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting method were used to identify the characteristics of proteins associated with sdLDL. An enzyme-linked immunosorbent assay (ELISA) method was developed and validated for the measurement of CK8 in plasma. Results: The validation of the CK8 ELISA method showed good analytical performance. The isolated sdLDL particles were verified with nondenaturing GGE with the apolipoprotein B component confirmed by Western immunoblotting. Confirmed by SDS-PAGE and Western immunoblotting, CK8 was associated with sdLDL. Two-tailed statistical analysis showed that CK8 and sdLDL particles were significantly higher in the high-risk CVD group compared to control group (P < 0.01 and P < 0.01, respectively). Conclusion: This study reports a novel association between CK8 and sdLDL in individuals with CVD who have a predominance of sdLDL. PMID:26713292

  1. Postpartum weight retention is associated with elevated ratio of oxidized LDL lipids to HDL-cholesterol.

    PubMed

    Puhkala, Jatta; Luoto, Riitta; Ahotupa, Markku; Raitanen, Jani; Vasankari, Tommi

    2013-12-01

    Oxidized LDL lipids (ox-LDL) are associated with lifestyle diseases such as cardiovascular diseases, metabolic syndrome and type 2 diabetes. The present study investigated how postpartum weight retention effects on ox-LDL and serum lipids. The study is a nested comparative research of a cluster-randomized controlled trial, NELLI (lifestyle and counselling during pregnancy). During early pregnancy (8-12 weeks) and 1 year postpartum, 141 women participated in measurements for determining of plasma lipids: total cholesterol (T-C), LDL-cholesterol (LDL-C), HDL-cholesterol (HDL-C), triacylglycerols (TAG) and ox-LDL. Subjects were stratified into tertiles (weight loss, unaltered weight and weight gain groups) based on their weight change from baseline to follow-up. Ox-LDL was determined by baseline level of conjugated dienes in LDL lipids. Among the group of weight gainers, concentration of TAG reduced less (-0.14 vs. -0.33, p = 0.002), HDL-C reduced more (-0.31 vs. -0.16, p = 0.003) and ox-LDL/HDL-C ratio increased (3.0 vs. -0.2, p = 0.003) when compared to group of weight loss. Both T-C and LDL-C elevated more (0.14 vs. -0.21, p = 0.008; 0.31 vs. 0.07, p = 0.015) and TAG and ox-LDL reduced less (-0.33 vs. 0.20, p = 0.033; -3.33 vs. -0.68, p = 0.026) in unaltered weight group compared to weight loss group. The women who gained weight developed higher TAG and ox-LDL/HDL-C ratio as compared to those who lost weight. Postpartum weight retention of 3.4 kg or more is associated with atherogenic lipid profile.

  2. Sex Differences in the Impact of the Mediterranean Diet on LDL Particle Size Distribution and Oxidation

    PubMed Central

    Bédard, Alexandra; Corneau, Louise; Lamarche, Benoît; Dodin, Sylvie; Lemieux, Simone

    2015-01-01

    Sex differences have been previously highlighted in the cardioprotective effects of the Mediterranean diet (MedDiet). The objective of this study was to investigate whether sex differences also exist with regard to LDL particle size distribution and oxidation. Participants were 37 men and 32 premenopausal women (24–53 years) with slightly elevated LDL-C concentrations (3.4–4.9 mmol/L) or total cholesterol/HDL-C ≥5.0. Variables were measured before and after a four-week isoenergetic MedDiet. Sex differences were found in response to the MedDiet for the proportion of medium LDL (255–260 Å) (p for sex-by-time interaction = 0.01) and small, dense LDL (sdLDL; <255 Å) (trend; p for sex-by-time interaction = 0.06), men experiencing an increase in the proportion of medium LDL with a concomitant reduction in the proportion of sdLDL, while an opposite trend was observed in women. A sex difference was also noted for estimated cholesterol concentrations among sdLDL (p for sex-by-time interaction = 0.03), with only men experiencing a reduction in response to the MedDiet. The MedDiet marginally reduced oxidized LDL (oxLDL) concentrations (p = 0.07), with no sex difference. Results suggest that short-termconsumption of the MedDiet leads to a favorable redistribution of LDL subclasses from smaller to larger LDL only in men. These results highlight the importance of considering sex issues in cardiovascular benefits of the MedDiet. PMID:25988764

  3. PCSK9-mediated degradation of the LDL receptor generates a 17 kDa C-terminal LDL receptor fragment.

    PubMed

    Tveten, Kristian; Strøm, Thea Bismo; Berge, Knut Erik; Leren, Trond P

    2013-06-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to the LDL receptor (LDLR) at the cell surface and reroutes the internalized LDLR to intracellular degradation. In this study, we have shown that PCSK9-mediated degradation of the full-length 160 kDa LDLR generates a 17 kDa C-terminal LDLR fragment. This fragment was not generated from mutant LDLRs resistant to PCSK9-mediated degradation or when degradation was prevented by chemicals such as ammonium chloride or the cysteine cathepsin inhibitor E64d. The observation that the 17 kDa fragment was only detected when the cells were cultured in the presence of the γ-secretase inhibitor DAPT indicates that this 17 kDa fragment undergoes γ-secretase cleavage within the transmembrane domain. The failure to detect the complementary 143 kDa ectodomain fragment is likely to be due to its rapid degradation in the endosomal lumen. The 17 kDa C-terminal LDLR fragment was also generated from a Class 5 mutant LDLR undergoing intracellular degradation. Thus, one may speculate that an LDLR with bound PCSK9 and a Class 5 LDLR with bound LDL are degraded by a similar mechanism that could involve ectodomain cleavage in the endosome.

  4. Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe.

    PubMed

    Thompson, Gilbert R; Catapano, Alberico; Saheb, Samir; Atassi-Dumont, Marielle; Barbir, Mahmoud; Eriksson, Mats; Paulweber, Bernhard; Sijbrands, Eric; Stalenhoef, Anton F; Parhofer, Klaus G

    2010-12-01

    Despite the use of currently available lipid-lowering therapies, a significant proportion of patients with severe hypercholesterolaemia do not reach treatment goals and consequently remain at increased risk for cardiovascular disease (CVD). On the basis of clinical experience, these patients tend to have the most severe forms of familial hypercholesterolaemia or markedly elevated LDL cholesterol (LDL-C) levels but are unable to tolerate statin therapy. LDL apheresis is currently the best treatment option (or treatment rescue) to bring these patients closer to therapeutic LDL objectives, and has been shown to reduce the risk of CVD along with LDL-C levels. However, criteria for LDL apheresis eligibility and the percentage of patients receiving treatment vary widely from country to country across Europe. Despite the proven benefits of LDL apheresis, access to this procedure remains limited because of its high cost and low availability, reflecting inherent limitations of this treatment modality. There is a need to both better define the patient population eligible for LDL apheresis and to create unified European guidelines governing the use of apheresis. In addition to improving access to apheresis where appropriate, new therapies are needed to further decrease LDL-C and reduce the ongoing CVD risk in patients with severe hypercholesterolaemia.

  5. Identification of candidate genes encoding an LDL-C QTL in baboons[S

    PubMed Central

    Karere, Genesio M.; Glenn, Jeremy P.; Birnbaum, Shifra; Hafizi, Sussan; Rainwater, David L.; Mahaney, Michael C.; VandeBerg, John L.; Cox, Laura A.

    2013-01-01

    Cardiovascular disease (CVD) is the leading cause of death in developed countries, and dyslipidemia is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple, related quantitative traits for serum LDL-cholesterol (LDL-C). Here we report differentially regulated hepatic genes encoding an LDL-C QTL that influences LDL-C levels in baboons. We performed hepatic whole-genome expression profiling for LDL-C-discordant baboons fed a high-cholesterol, high-fat (HCHF) diet for seven weeks. We detected expression of 117 genes within the QTL 2-LOD support interval. Three genes were differentially expressed in low LDL-C responders and 8 in high LDL-C responders in response to a HCHF diet. Seven genes (ACVR1B, CALCOCO1, DGKA, ERBB3, KRT73, MYL6B, TENC1) showed discordant expression between low and high LDL-C responders. To prioritize candidate genes, we integrated miRNA and mRNA expression profiles using network tools and found that four candidates (ACVR1B, DGKA, ERBB3, TENC1) were miRNA targets and that the miRNAs were inversely expressed to the target genes. Candidate gene expression was validated using QRT-PCR and Western blotting. This study reveals candidate genes that influence variation in LDL-C in baboons and potential genetic mechanisms for further investigation. PMID:23596326

  6. Oxidized-LDL induce morphological changes and increase stiffness of endothelial cells

    SciTech Connect

    Chouinard, Julie A.; Grenier, Guillaume; Khalil, Abdelouahed; Vermette, Patrick

    2008-10-01

    There is increasing evidence suggesting that oxidized low-density lipoproteins (ox-LDL) play a critical role in endothelial injury contributing to the age-related physio-pathological process of atherosclerosis. In this study, the effects of native LDL and ox-LDL on the mechanical properties of living human umbilical vein endothelial cells (HUVEC) were investigated by atomic force microscopy (AFM) force measurements. The contribution of filamentous actin (F-actin) and vimentin on cytoskeletal network organization were also examined by fluorescence microscopy. Our results revealed that ox-LDL had an impact on the HUVEC shape by interfering with F-actin and vimentin while native LDL showed no effect. AFM colloidal force measurements on living individual HUVEC were successfully used to measure stiffness of cells exposed to native and ox-LDL. AFM results demonstrated that the cell body became significantly stiffer when cells were exposed for 24 h to ox-LDL while cells exposed for 24 h to native LDL displayed similar rigidity to that of the control cells. Young's moduli of LDL-exposed HUVEC were calculated using two models. This study thus provides quantitative evidence on biomechanical mechanisms related to endothelial cell dysfunction and may give new insight on strategies aiming to protect endothelial function in atherosclerosis.

  7. HDL/LDL ratio: a useful parameter for separation of pleural transudates from exudates.

    PubMed

    Köktürk, Oğuz; Ulukavak Ciftci, Tansu; Firat, Hikmet; Firat, Serap

    2005-01-01

    The first diagnostic step in pleural effusions is the separation of transudates from exudates. We aimed in present study to investigate the value of HDL/LDL ratio for distinguishing between pleural exudates and transudates. Pleural fluids (PF)from 121 patients, including 28 transudates and 93 exudates were analyzed. The levels of cholesterol, HDL cholesterol and LDL cholesterol in PF were measured. The HDL/LDL ratio was calculated. HDL/LDL ratio found significantly higher in transudates than exudates (p= 0.001). Receiver operating characteristic (ROC) curves were generated and the cut off points determined to the highest level of accuracy and precision. The HDL/LDL ratio was to maximize sensitivity over specificity in the diagnosis of a transudative effusion. The usefulness of HDL/LDL ratio for identifying transudates was evaluated in terms of sensitivity and specificity. The value of pleural HDL/LDL ratio that best differentiated between transudates and exudates was 0.6 (sensitivity 89%, and specificity of 79%). Measurement of HDL and LDL in PF and calculating of HDL/LDL ratio can be proposed to aid for differentiation between pleural exudates and transudates with advantage of not requiring serum levels.

  8. Influence of oxidized low-density lipoproteins (LDL) on the viability of osteoblastic cells.

    PubMed

    Brodeur, Mathieu R; Brissette, Louise; Falstrault, Louise; Ouellet, Pascale; Moreau, Robert

    2008-02-15

    Cardiovascular diseases have recently been noted as potential risk factors for osteoporosis development. Although it is poorly understood how these two pathologies are related, it is a known fact that oxidized low-density lipoproteins (OxLDL) constitute potential determinants for both of them. The current study investigated the metabolism of OxLDL by osteoblasts and its effect on osteoblastic viability. The results obtained show that OxLDL are internalized but not degraded by osteoblasts while they can selectively transfer their CE to these cells. It is also demonstrated that OxLDL induce proliferation at low concentrations but cell death at high concentrations. This reduction of osteoblast viability was associated with lysosomal membrane damage caused by OxLDL as demonstrated by acridine orange relocalization. Accordingly, chloroquine, an inhibitor of lysosomal activity, accentuated cell death induced by OxLDL. Finally, we demonstrate that osteoblasts have the capacity to oxidize LDL and thereby potentially increase the local concentration of OxLDL. Overall, the current study confirms the potential role of OxLDL in the development of osteoporosis given its influence on osteoblastic viability.