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Sample records for electronegative ldl inhibit

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. Exendin-4 ameliorates oxidized-LDL-induced inhibition of macrophage migration in vitro via the NF-κB pathway

    PubMed Central

    Ma, Ge-fei; Chen, Song; Yin, Lei; Gao, Xiang-dong; Yao, Wen-bing

    2014-01-01

    Aim: To investigate the effects of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 on oxidized low-density lipoprotein (ox-LDL)-induced inhibition of macrophage migration and the mechanisms underlying the effects of exendin-4. Methods: Primary peritoneal macrophages were extracted from the peritoneal cavity of mice treated with 3% thioglycollate (2 mL, ip). Migration of the macrophages was examined using a cell migration assay. Macrophage migration-related factors including leptin-like ox-LDL receptor (LOX-1), cyclooxygenase 2 (COX-2), tumor necrosis factor (TNF)-α, interleukin-1 (IL-1)β, matrix metalloproteinase-2 (MMP-2), intercellular adhesion molecule (ICAM)-1 and macrophage migration inhibitory factor (MIF) were measured using semi-quantitative RT-PCR. Expression of MIF and ICAM-1 proteins was examined with ELISA. Gelatin zymography was used to evaluate the activity of MMP-9. Activation of the NF-κB pathway was determined by confocal laser scanning microscopy. Results: Treatment of the macrophages with ox-LDL (50 μg/mL) markedly suppressed the macrophage migration. Furthermore, ox-LDL treatment substantially increased the expression of the macrophage migration-related factors, the activity of MMP-9 and the translocation of the NF-κB p65 subunit. These effects of ox-LDL were significantly ameliorated by pretreatment with the specific NF-κB inhibitor ammonium pyrrolidine dithiocarbamate (100 μmol/L). These effects of ox-LDL were also significantly ameliorated by pretreatment with exendin-4 (25 and 50 nmol/L). Conclusion: Exendin-4 ameliorates the inhibition of ox-LDL on macrophage migration in vitro, via suppressing ox-LDL-induced expression of ICAM-1 and MIF, which is probably mediated by the NF-κB pathway. PMID:24335838

  15. 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

  16. 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)

  17. 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.

  18. 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.

  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. 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.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

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

    PubMed

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

    2015-04-23

    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.

  8. 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.

  9. 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

  10. 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.

  11. 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

  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. 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.

  14. 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

  15. 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(-).

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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.

  2. 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…

  3. 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.

  4. LDL Cholesterol Test

    MedlinePlus

    ... products and services. Advertising & Sponsorship: Policy | Opportunities LDL Cholesterol Share this page: Was this page helpful? Also ... LDL; LDL-C Formal name: Low-Density Lipoprotein Cholesterol Related tests: Cholesterol ; HDL Cholesterol ; Triglycerides ; Lipid Profile ; ...

  5. LDL Particle Testing

    MedlinePlus

    ... assessing cardiac risk in people who have a personal or family history of heart disease at a young age, especially if their total cholesterol and LDL cholesterol (LDL-C) values are not significantly elevated. LDL subfraction testing is ...

  6. 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)

  7. 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.

  8. 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

  9. 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.

  10. 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.)

  11. S-nitrosylation of ARH is required for LDL uptake by the LDL receptor.

    PubMed

    Zhao, Zhenze; Pompey, Shanica; Dong, Hongyun; Weng, Jian; Garuti, Rita; Michaely, Peter

    2013-06-01

    The LDL receptor (LDLR) relies upon endocytic adaptor proteins for internalization of lipoproteins. The results of this study show that the LDLR adaptor autosomal recessive hypercholesterolemia protein (ARH) requires nitric oxide to support LDL uptake. Nitric oxide nitrosylates ARH at C199 and C286, and these posttranslational modifications are necessary for association of ARH with the adaptor protein 2 (AP-2) component of clathrin-coated pits. In the absence of nitrosylation, ARH is unable to target LDL-LDLR complexes to coated pits, resulting in poor LDL uptake. The role of nitric oxide on LDLR function is specific for ARH because inhibition of nitric oxide synthase activity impairs ARH-supported LDL uptake but has no effect on other LDLR-dependent lipoprotein uptake processes, including VLDL remnant uptake and dab2-supported LDL uptake. These findings suggest that cells that depend upon ARH for LDL uptake can control which lipoproteins are internalized by their LDLRs through changes in nitric oxide.

  12. 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.

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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)

  19. 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…

  20. 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

  1. 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

  2. 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.

  3. 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

  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. 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.

  6. [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.

  7. 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.

  8. 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.

  9. 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

  10. 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.

  11. 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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. Synthetic LDL as targeted drug delivery vehicle

    SciTech Connect

    Forte, Trudy M; Nikanjam, Mina

    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.

  17. 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

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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''.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. LRP6 protein regulates low density lipoprotein (LDL) receptor-mediated LDL uptake.

    PubMed

    Ye, Zhi-jia; Go, Gwang-Woong; Singh, Rajvir; Liu, Wenzhong; Keramati, Ali Reza; Mani, Arya

    2012-01-06

    Genetic variations in LRP6 gene are associated with high serum LDL cholesterol levels. We have previously shown that LDL clearance in peripheral B-lymphocytes of the LRP6(R611C) mutation carriers is significantly impaired. In this study we have examined the role of wild type LRP6 (LRP6(WT)) and LRP6(R611C) in LDL receptor (LDLR)-mediated LDL uptake. LDL binding and uptake were increased when LRP6(WT) was overexpressed and modestly reduced when it was knocked down in LDLR-deficient CHO (ldlA7) cells. These findings implicated LRP6 in LDLR-independent cellular LDL binding and uptake. However, LRP6 knockdown in wild type CHO cells resulted in a much greater decline in LDL binding and uptake compared with CHO-ldlA7 cells, suggesting impaired function of the LDLR. LDLR internalization was severely diminished when LRP6 was knocked down and was restored after LRP6 was reintroduced. Further analysis revealed that LRP6(WT) forms a complex with LDLR, clathrin, and ARH and undergoes a clathrin-mediated internalization after stimulation with LDL. LDLR and LRP6 internalizations as well as LDL uptake were all impaired in CHO-k1 cells expressing LRP6(R611C). These studies identify LRP6 as a critical modulator of receptor-mediated LDL endocytosis and introduce a mechanism by which variation in LRP6 may contribute to high serum LDL levels.

  2. 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.

  3. 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

  4. 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.

  5. 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.

  6. 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.

  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. 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.

  9. 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.

  10. 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

  11. 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

  12. 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

  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. 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

  15. 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)

  16. 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.

  17. 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.

  18. 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)

  19. Effect of collision parameters in electronegative plasma sheath with two species of positive ions

    SciTech Connect

    Moulick, R.; Goswami, K. S.; Mahanta, M. K.

    2013-09-15

    The effect of ion neutral collision is shown for two species of positive ions in electronegative plasma. The ion neutral collision is modeled using power law of collision cross section. It is a usual case for processing plasma to have two species of positive ions and hence we attempt to study the dynamics of the two species of ions inside the collisional sheath of electronegative plasma.

  20. 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

  1. 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

  2. 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

  3. 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.

  4. 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).

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  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. 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

  2. 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.

  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. 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.

  5. 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%.

  6. 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.

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. The composition and metabolism of large and small LDL

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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...

  13. 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

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. 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.

  20. 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]…

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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

  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. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. [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.

  15. 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

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  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. 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.

  3. 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.

  4. Adaptor protein ARH is recruited to the plasma membrane by low density lipoprotein (LDL) binding and modulates endocytosis of the LDL/LDL receptor complex in hepatocytes.

    PubMed

    Sirinian, Maria Isabella; Belleudi, Francesca; Campagna, Filomena; Ceridono, Mara; Garofalo, Tina; Quagliarini, Fabiana; Verna, Roberto; Calandra, Sebastiano; Bertolini, Stefano; Sorice, Maurizio; Torrisi, Maria Rosaria; Arca, Marcello

    2005-11-18

    ARH is a newly discovered adaptor protein required for the efficient activity of low density lipoprotein receptor (LDLR) in selected tissues. Individuals lacking ARH have severe hypercholesterolemia due to an impaired hepatic clearance of LDL. It has been demonstrated that ARH is required for the efficient internalization of the LDL-LDLR complex and to stabilize the association of the receptor with LDL in Epstein-Barr virus-immortalized B lymphocytes. However, little information is available on the role of ARH in liver cells. Here we provide evidence that ARH is codistributed with LDLR on the basolateral area in confluent HepG2-polarized cells. This distribution is not modified by the overexpression of LDLR. Conversely, the activation of the LDLR-mediated endocytosis, but not the binding of LDL to LDLR, promotes a significant colocalization of ARH with LDL-LDLR complex that peaked at 2 min at 37 degrees C. To further assess the role of ARH in LDL-LDLR complex internalization, we depleted ARH protein using the RNA interference technique. Twenty-four hours after transfection with ARH-specific RNA interference, ARH protein was depleted in HepG2 cells by more than 70%. Quantitative immunofluorescence analysis revealed that the depletion of ARH caused about 80% reduction in LDL internalization. Moreover, our findings indicate that ARH is associated with other proteins of the endocytic machinery. We suggest that ARH is an endocytic sorting adaptor that actively participates in the internalization of the LDL-LDLR complex, possibly enhancing the efficiency of its packaging into the endocytic vesicles.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. 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)

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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.

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. [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.

  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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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.

  8. 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.

  9. Investigation of Radio Frequency Discharges and Langmuir Probe Diagnostic Methods in a Fast Flowing Electronegative Background Gas

    DTIC Science & Technology

    2007-12-01

    the equations 1.43, 1.44, and 1.45, can be solved using a Runge - Kutta or other standard numerical techniques with the results of the solution to the...INVESTIGATION OF RADIO FREQUENCY DISCHARGES AND LANGMUIR PROBE DIAGNOSTIC METHODS IN A FAST FLOWING...AFIT/DS/ENP/DSP-04J INVESTIGATION OF RADIO FREQUENCY DISCHARGES AND LANGMUIR PROBE DIAGNOSTIC METHODS IN A FAST FLOWING ELECTRONEGATIVE

  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. 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).

  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. 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.

  16. 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).

  17. 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

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia.

    PubMed

    Soufi, Muhidien; Rust, Stephan; Walter, Michael; Schaefer, Juergen R

    2013-05-25

    Familial hypercholesterolemia (FH) results from impaired catabolism of plasma low density lipoproteins (LDL), thus leading to high cholesterol, atherosclerosis, and a high risk of premature myocardial infarction. FH is commonly caused by defects of the LDL receptor or its main ligand apoB, together mediating cellular uptake and clearance of plasma LDL. In some cases FH is inherited by mutations in the genes of PCSK9 and LDLRAP1 (ARH) in a dominant or recessive trait. The encoded proteins are required for LDL receptor stability and internalization within the LDLR pathway. To detect the underlying genetic defect in a family of Turkish descent showing unregular inheritance of severe FH, we screened the four candidate genes by denaturing gradient gel electrophoresis (DGGE) mutation analysis. We identified different combinatory mixtures of LDLR- and LDLRAP1-gene defects as the cause for severe familial hypercholesterolemia in this family. We also show for the first time that a heterozygous LDLR mutation combined with a homozygous LDLRAP1 mutation produces a more severe hypercholesterolemia phenotype in the same family than a homozygous LDLR mutation alone.

  3. 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

  4. 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.

  5. 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

  6. 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.)

  7. 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.

  8. 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

  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. 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.

  11. 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

  12. 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.

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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

  20. 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.

  1. 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.

  2. The modular adaptor protein ARH is required for low density lipoprotein (LDL) binding and internalization but not for LDL receptor clustering in coated pits.

    PubMed

    Michaely, Peter; Li, Wei-Ping; Anderson, Richard G W; Cohen, Jonathan C; Hobbs, Helen H

    2004-08-06

    ARH is an adaptor protein required for efficient endocytosis of low density lipoprotein (LDL) receptors (LDLRs) in selected tissues. Individuals lacking ARH (ARH-/-) have severe hypercholesterolemia due to impaired hepatic clearance of LDL. Immortalized lymphocytes, but not fibroblasts, from ARH-deficient subjects fail to internalize LDL. To further define the role of ARH in LDLR function, we compared the subcellular distribution of the LDLR in lymphocytes from normal and ARH-/- subjects. In normal lymphocytes LDLRs were predominantly located in intracellular compartments, whereas in ARH-/- cells the receptors were almost exclusively on the plasma membrane. Biochemical assays and quantification of LDLR by electron microscopy indicated that ARH-/- lymphocytes had >20-fold more LDLR on the cell surface and a approximately 27-fold excess of LDLR outside of coated pits. The accumulation of LDLR on the cell surface was not due to failure of receptors to localize in coated pits since the number of LDLRs in coated pits was similar in ARH-/- and normal cells. Despite the dramatic increase in cell surface receptors, LDL binding was only 2-fold higher in the ARH-/- lymphocytes. These findings indicate that ARH is required not only for internalization of the LDL.LDLR complex but also for efficient binding of LDL to the receptor and suggest that ARH stabilizes the associations of the receptor with LDL and with the invaginating portion of the budding pit, thereby increasing the efficiency of LDL internalization.

  3. 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.

  4. 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

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. Large eddy simulation of LDL surface concentration in a subject specific human aorta.

    PubMed

    Lantz, Jonas; Karlsson, Matts

    2012-02-02

    The development of atherosclerosis is correlated to the accumulation of lipids in the arterial wall, which, in turn, may be caused by the build-up of low-density lipoproteins (LDL) on the arterial surface. The goal of this study was to model blood flow within a subject specific human aorta, and to study how the LDL surface concentration changed during a cardiac cycle. With measured velocity profiles as boundary conditions, a scale-resolving technique (large eddy simulation, LES) was used to compute the pulsatile blood flow that was in the transitional regime. The relationship between wall shear stress (WSS) and LDL surface concentration was investigated, and it was found that the accumulation of LDL correlated well with WSS. In general, regions of low WSS corresponded to regions of increased LDL concentration and vice versa. The instantaneous LDL values changed significantly during a cardiac cycle; during systole the surface concentration was low due to increased convective fluid transport, while in diastole there was an increased accumulation of LDL on the surface. Therefore, the near-wall velocity was investigated at four representative locations, and it was concluded that in regions with disturbed flow the LDL concentration had significant temporal changes, indicating that LDL accumulation is sensitive to not only the WSS but also near-wall flow.

  1. Regulation of small dense LDL concentration in Korean and Scottish men and women.

    PubMed

    Cho, Hong Keun; Shin, Gilja; Ryu, Sung Kee; Jang, Yangsoo; Day, Stephen P; Stewart, Grace; Packard, Chris J; Shepherd, James; Caslake, Muriel J

    2002-09-01

    Small dense LDL is now emerging as an important risk factor for coronary artery disease. The amount of the LDL III has been reported to differ between ethnic groups. To investigate differences in the distribution of LDL subfractions between Korean and Scottish populations, we measured the plasma concentration and percent distribution of three major LDL subfractions in age-and sex-matched, middle aged, healthy 124 Korean and Scottish subjects (32 Korean men vs. 32 Scottish men; 30 Korean women vs. 30 Scottish women). Body mass index and waist circumference did not differ between the two ethnic groups. Total cholesterol and LDL cholesterol concentrations were higher in Scottish men compared with Korean men (P<0.01), while plasma triglyceride concentration was higher in Korean men and women (P<0.01 in men, P<0.05 in women). HDL cholesterol concentrations in both Korean men and women were lower than that of their Scottish counterparts (P<0.05 in men; P<0.001 in women). Korean men had lower concentrations of total LDL (242+/-65 vs. 325+/-122 mg/dl, P<0.01), LDL I (24+/-18 vs. 60+/-36 mg/dl, P<0.001) and LDL II (110+/-56 vs. 196+/-78 mg/dl, P<0.001). In contrast, LDL III concentration was markedly higher in Korean men (108+/-75 vs. 70+/-65 mg/dl, P<0.05). Likewise, the percent of LDL I (10.0+/-7.3 vs. 19.1+/-10.1%, P<0.001) and LDL II (47.2+/-20.7 vs. 60.1+/-10.9%, P<0.01) were lower in Korean men, while that of LDL III was higher (42.8+/-24.9 vs. 20.8+/-15.0%, P<0.001). In the female population, there were no differences in total LDL and LDL I concentrations between Korean and Scottish. LDL II concentration was lower in Korean women (106+/-53 vs. 151+/-57 mg/dl, P<0.01). Korean women showed a higher percent of LDL III (24.8+/-24.7 vs. 14.2+/-5.9%, P<0.05) and a lower LDL II (47.8+/-19.1 vs. 61.0+/-10.0%, P<0.01). Multiple linear regression revealed that plasma triglyceride concentration was the most important determinant of the LDL III subfraction concentration in

  2. [Association between food behavior and hypercholesterolemia-LDL in university students].

    PubMed

    Salazar Ruiz, Erika Nohemi; Márquez Sandoval, Yolanda Fabiola; Vizmanos Lamotte, Bárbara; Altamirano Martínez, Martha Betzaida; Salgado Bernabé, Aralia Berenice; Salgado Goytia, Lorenzo; Muñoz Valle, José Francisco; Parra Rojas, Isela

    2015-06-01

    Introducción: la hipercolesterolemia-LDL (H-LDL) se asocia a mayor riesgo de enfermedad cardiovascular. La asociacion entre H-LDL y alimentacion se ha centrado en aspectos nutrimentales. El estudio de la asociacion entre el comportamiento alimentario (CA) y la H-LDL en estudiantes universitarios podria brindar elementos de correccion y/o prevencion nutricional en esta poblacion. Objetivo: evaluar la asociacion entre CA e H-LDL en estudiantes universitarios. Métodos: estudio transversal realizado en una muestra de 167 estudiantes de la Universidad Autonoma de Guerrero, Mexico. Se midio el colesterol-LDL serico, considerandose hipercolesterolemia una concentracion ≥100 mg/dL. El CA se evaluo mediante un cuestionario previamente validado. La asociacion entre CA e H-LDL se determino con una regresion logistica bivariada, ajustando por sexo, edad, nivel socioeconomico, tabaquismo, ingesta de energia, actividad fisica, presencia o no de obesidad y antecedentes familiares. Resultados: consumir el almuerzo (colacion matutina) se asocio con un 63% de menos riesgo de H-LDL (OR 0,37; 95% IC 0,15, 0,90). Ingerir alimentos fuera de casa una o dos veces a la semana, se asocio con cuatro veces mas riesgo de H-LDL (R 5,14; 95% IC 1,12, 23,62). Los sujetos que referian consumir alimentos en exceso (1 o 2, y 3 o mas veces/semana) tuvieron mayor riesgo de H-LDL (OR 3,26; 95% IC 1,10, 9,64 y OR 10,52; 95% IC 2,66, 41,60, respectivamente). Conclusiones: algunos CA habituales de los estudiantes universitarios de Guerrero implican mayor riesgo de H-LDL. Por ello, promover acciones correctivas y/o preventivas centradas en estos CA podria mejorar la salud de esta poblacion.

  3. Nox2 Modification of LDL Is Essential for Optimal Apolipoprotein B-mediated Control of agr Type III Staphylococcus aureus Quorum-sensing

    PubMed Central

    Hall, Pamela R.; Elmore, Bradley O.; Spang, Cynthia H.; Alexander, Susan M.; Manifold-Wheeler, Brett C.; Castleman, Moriah J.; Daly, Seth M.; Peterson, M. Michal; Sully, Erin K.; Femling, Jon K.; Otto, Michael; Horswill, Alexander R.; Timmins, Graham S.; Gresham, Hattie D.

    2013-01-01

    Staphylococcus aureus contains an autoinducing quorum-sensing system encoded within the agr operon that coordinates expression of virulence genes required for invasive infection. Allelic variation within agr has generated four agr specific groups, agr I–IV, each of which secretes a distinct autoinducing peptide pheromone (AIP1-4) that drives agr signaling. Because agr signaling mediates a phenotypic change in this pathogen from an adherent colonizing phenotype to one associated with considerable tissue injury and invasiveness, we postulated that a significant contribution to host defense against tissue damaging and invasive infections could be provided by innate immune mechanisms that antagonize agr signaling. We determined whether two host defense factors that inhibit AIP1-induced agrI signaling, Nox2 and apolipoprotein B (apoB), also contribute to innate control of AIP3-induced agrIII signaling. We hypothesized that apoB and Nox2 would function differently against AIP3, which differs from AIP1 in amino acid sequence and length. Here we show that unlike AIP1, AIP3 is resistant to direct oxidant inactivation by Nox2 characteristic ROS. Rather, the contribution of Nox2 to defense against agrIII signaling is through oxidation of LDL. ApoB in the context of oxLDL, and not LDL, provides optimal host defense against S. aureus agrIII infection by binding the secreted signaling peptide, AIP3, and preventing expression of the agr-driven virulence factors which mediate invasive infection. ApoB within the context of oxLDL also binds AIP 1-4 and oxLDL antagonizes agr signaling by all four agr alleles. Our results suggest that Nox2-mediated oxidation of LDL facilitates a conformational change in apoB to one sufficient for binding and sequestration of all four AIPs, demonstrating the interdependence of apoB and Nox2 in host defense against agr signaling. These data reveal a novel role for oxLDL in host defense against S. aureus quorum-sensing signaling. PMID:23459693

  4. Association of LDL subfractions with clinical cardiovascular outcomes: A systematic review

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Context: Low-density lipoprotein (LDL) subfractions have been proposed as an independent risk factor for cardiovascular disease (CVD). Objective: Systematically review the relationship between LDL subfractions and incidence and progression of CVD. Data Sources: Medline, CAB Abstracts, and Cochrane C...

  5. Platelet Activation by Low Concentrations of Intact Oxidized LDL Particles Involves the PAF Receptor

    PubMed Central

    Chen, Rui; Chen, Xi; Salomon, Robert G.; McIntyre, Thomas M.

    2008-01-01

    Objective Mitochondrial depolarization aids platelet activation. Oxidized LDL (oxLDL) contains the medium length oxidatively truncated phospholipid hexadecyl azelaoyl-lysoPAF (HAz-LPAF) that disrupts mitochondrial function in nucleated cells, so oxLDL may augment platelet activation. Methods and Results Flow cytometry showed intact oxLDL particles synergized with sub-threshold amounts of soluble agonists to increase intracellular Ca++, and initiate platelet aggregation and surface expression of activated gpIIb/IIIa and P-selectin. oxLDL also induced aggregation and increased intracellular Ca++ in FURA2-labeled cells by itself at low, although not higher, concentrations. HAz-LPAF, alone and in combination with sub-stimulatory amounts of thrombin, rapidly increased cytoplasmic Ca++ and initiated aggregation. HAz-LPAF depolarized mitochondria in intact platelets, but this required concentrations beyond those that directly activated platelets. An unexpectedly large series of chemically pure truncated phospholipids generated by oxidative fragmentation of arachidonoyl-, docosahexaneoyl-, or linoleoyl alkyl phospholipids were platelet agonists. The PAF receptor, thought to effectively recognize only phospholipids with very short sn-2 residues, was essential for platelet activation because PAF receptor agonists blocked signaling by all these medium length phospholipids and oxLDL. Conclusions Intact oxLDL particles activate platelets through the PAF receptor, and the PAF receptor responds to a far wider range of oxidized phospholipids in oxLDL than anticipated. PMID:19112165

  6. The hydrophobic tunnel present in LOX-1 is essential for oxidized LDL recognition and binding.

    PubMed

    Francone, Omar L; Tu, Meihua; Royer, Lori J; Zhu, Jian; Stevens, Kimberly; Oleynek, Joseph J; Lin, Zhiwu; Shelley, Lorraine; Sand, Thomas; Luo, Yi; Kane, Christopher D

    2009-03-01

    Lectin-like oxidized LDL (ox-LDL) receptor-1 (LOX-1) is a type-II transmembrane protein that belongs to the C-type lectin family of molecules. LOX-1 acts as a cell surface endocytosis receptor and mediates the recognition and internalization of ox-LDL by vascular endothelial cells. Internalization of ox-LDL by LOX-1 results in a number of pro-atherogenic cellular responses implicated in the development and progression of atherosclerosis. In an effort to elucidate the functional domains responsible for the binding of ox-LDL to the receptor, a series of site-directed mutants were designed using computer modeling and X-ray crystallography to study the functional role of the hydrophobic tunnel present in the LOX-1 receptor. The isoleucine residue (I(149)) sitting at the gate of the channel was replaced by phenylalanine, tyrosine, or glutamic acid to occlude the channel opening and restrict the docking of ligands to test its functional role in the binding of ox-LDL. The synthesis, intracellular processing, and cellular distribution of all mutants were identical to those of wild type, whereas there was a marked decrease in the ability of the mutants to bind ox-LDL. These studies suggest that the central hydrophobic tunnel that extends through the entire LOX-1 molecule is a key functional domain of the receptor and is critical for the recognition of modified LDL.

  7. Protective effect of the silkworm protein 30Kc6 on human vascular endothelial cells damaged by oxidized low density lipoprotein (Ox-LDL).

    PubMed

    Yu, Wei; Ying, Huihui; Tong, Fudan; Zhang, Chen; Quan, Yanping; Zhang, Yaozhou

    2013-01-01

    Although the 30K family proteins are important anti-apoptotic molecules in silkworm hemolymph, the underlying mechanism remains to be investigated. This is especially the case in human vascular endothelial cells (HUVECs). In this study, a 30K protein, 30Kc6, was successfully expressed and purified using the Bac-to-Bac baculovirus expression system in silkworm cells. Furthermore, the 30Kc6 expressed in Escherichia coli was used to generate a polyclonal antibody. Western blot analysis revealed that the antibody could react specifically with the purified 30Kc6 expressed in silkworm cells. The In vitro cell apoptosis model of HUVEC that was induced by oxidized low density lipoprotein (Ox-LDL) and in vivo atherosclerosis rabbit model were constructed and were employed to analyze the protective effects of the silkworm protein 30Kc6 on these models. The results demonstrated that the silkworm protein 30Kc6 significantly enhanced the cell viability in HUVEC cells treated with Ox-LDL, decreased the degree of DNA fragmentation and markedly reduced the level of 8-isoprostane. This could be indicative of the silkworm protein 30Kc6 antagonizing the Ox-LDL-induced cell apoptosis by inhibiting the intracellular reactive oxygen species (ROS) generation. Furthermore, Ox-LDL activated the cell mitogen activated protein kinases (MAPK), especially JNK and p38. As demonstrated with Western analysis, 30Kc6 inhibited Ox-LDL-induced cell apoptosis in HUVEC cells by preventing the MAPK signaling pathways. In vivo data have demonstrated that oral feeding of the silkworm protein 30Kc6 dramatically improved the conditions of the atherosclerotic rabbits by decreasing serum levels of total triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and total cholesterol (TC). Furthermore, 30Kc6 alleviated the extent of lesions in aorta and liver in the atherosclerotic rabbits. These data are not only helpful in understanding the anti

  8. Correlation between pretreatment serum LDL-cholesterol levels and prognosis in nasopharyngeal carcinoma patients

    PubMed Central

    Tang, Qiu; Hu, Qiao-Ying; Piao, Yong-feng; Hua, Yong-Hong

    2016-01-01

    Purpose To investigate the correlations between long-term survival outcomes in patients with nasopharyngeal carcinoma (NPC) and pretreatment serum low-density lipoprotein cholesterol (LDL-C) levels. Patients and methods Between January 2008 and December 2011, 935 patients with newly diagnosed NPC who were treated with intensity-modulated radiation therapy were included in this retrospective clinical analysis. Patients were divided into two groups based on pretreatment LDL-C levels: normal LDL-C (≤3.64 mmol/L; n=816) and elevated LDL-C (>3.64 mmol/L; n=119). Associations between pretreatment LDL-C levels and treatment outcome were analyzed by univariate and multivariate analyses. Results The overall patient follow-up rate was 95.1%, and 726 patients received more than 5 years of follow-up. Five-year overall survival (OS), local control (LC), and distant metastasis-free survival (DMFS) rates of the entire patient population were 87.1%, 91.1%, and 87.2%, respectively. Rates of 5-year OS, LC, and DMFS for the elevated versus normal LDL-C groups were 77.0% vs 89.1% (P<0.001), 85.8% vs 91.9% (P=0.041), and 81.1% vs 88.1% (P=0.038), respectively. Compared with normal LDL-C levels, elevated LDL-C levels were identified as an independent prognostic factor of a poorer OS (hazard ratio [HR] =2.171; 95% confidence interval [CI] =1.424–3.309), LC rate (HR =1.762; 95% CI =1.021–3.942), and DMFS (HR =1.594; 95% CI =1.003–2.532). Conclusion This study found that elevated pretreatment LDL-C levels are negative prognostic indicators of NPC. Elevated LDL-C levels may be useful indicators of locoregional control and distant metastasis in NPC patients. PMID:27217776

  9. Implication of low HDL-c levels in patients with average LDL-c levels: a focus on oxidized LDL, large HDL subpopulation, and adiponectin.

    PubMed

    Mascarenhas-Melo, Filipa; Sereno, José; Teixeira-Lemos, Edite; Marado, Daniela; Palavra, Filipe; Pinto, Rui; Rocha-Pereira, Petronila; Teixeira, Frederico; Reis, Flávio

    2013-01-01

    To evaluate the impact of low levels of high density lipoprotein cholesterol (HDL-c) on patients with LDL-c average levels, focusing on oxidative, lipidic, and inflammatory profiles. Patients with cardiovascular risk factors (n = 169) and control subjects (n = 73) were divided into 2 subgroups, one of normal HDL-c and the other of low HDL-c levels. The following data was analyzed: BP, BMI, waist circumference and serum glucose Total-c, TGs, LDL-c, oxidized LDL, total HDL-c and subpopulations (small, intermediate, and large), paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF- α , adiponectin, VEGF, and iCAM1. In the control subgroup with low HDL-c levels, significantly higher values of BP and TGs and lower values of PON1 activity and adiponectin were found, versus control normal HDL-c subgroup. However, differences in patients' subgroups were clearly more pronounced. Indeed, low HDL-c subgroup presented increased HbA1c, TGs, non-HDL-c, Ox-LDL, hsCRP, VEGF, and small HDL-c and reduced adiponectin and large HDL. In addition, Ox-LDL, large-HDL-c, and adiponectin presented interesting correlations with classical and nonclassical markers, mainly in the normal HDL-c patients' subgroup. In conclusion, despite LDL-c average levels, low HDL-c concentrations seem to be associated with a poor cardiometabolic profile in a population with cardiovascular risk factors, which is better evidenced by traditional and nontraditional CV biomarkers, including Ox-LDL, large HDL-c, and adiponectin.

  10. Arsenic augments the uptake of oxidized LDL by upregulating the expression of lectin-like oxidized LDL receptor in mouse aortic endothelial cells

    SciTech Connect

    Hossain, Ekhtear; Ota, Akinobu; Karnan, Sivasundaram; Damdindorj, Lkhagvasuren; Takahashi, Miyuki; Konishi, Yuko; Konishi, Hiroyuki; Hosokawa, Yoshitaka

    2013-12-15

    Although chronic arsenic exposure is a well-known risk factor for cardiovascular diseases, including atherosclerosis, the molecular mechanism underlying arsenic-induced atherosclerosis remains obscure. Therefore, this study aimed to elucidate this molecular mechanism. We examined changes in the mRNA level of the lectin-like oxidized LDL (oxLDL) receptor (LOX-1) in a mouse aortic endothelial cell line, END-D, after sodium arsenite (SA) treatment. SA treatment significantly upregulated LOX-1 mRNA expression; this finding was also verified at the protein expression level. Flow cytometry and fluorescence microscopy analyses showed that the cellular uptake of fluorescence (Dil)-labeled oxLDL was significantly augmented with SA treatment. In addition, an anti-LOX-1 antibody completely abrogated the augmented uptake of Dil-oxLDL. We observed that SA increased the levels of the phosphorylated forms of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB)/p65. SA-induced upregulation of LOX-1 protein expression was clearly prevented by treatment with an antioxidant, N-acetylcysteine (NAC), or an NF-κB inhibitor, caffeic acid phenethylester (CAPE). Furthermore, SA-augmented uptake of Dil-oxLDL was also prevented by treatment with NAC or CAPE. Taken together, our results indicate that arsenic upregulates LOX-1 expression through the reactive oxygen species-mediated NF-κB signaling pathway, followed by augmented cellular oxLDL uptake, thus highlighting a critical role of the aberrant LOX-1 signaling pathway in the pathogenesis of arsenic-induced atherosclerosis. - Highlights: • Sodium arsenite (SA) increases LOX-1 expression in mouse aortic endothelial cells. • SA enhances cellular uptake of oxidized LDL in dose-dependent manner. • SA-induced ROS generation enhances phosphorylation of NF-κB. • SA upregulates LOX-1 expression through ROS-activated NF-κB signaling pathway.

  11. LDL of Taiwanese vegetarians are less oxidizable than those of omnivores.

    PubMed

    Lu, S C; Wu, W H; Lee, C A; Chou, H F; Lee, H R; Huang, P C

    2000-06-01

    The vegetarians in Taiwan consume diets high in polyunsaturated fatty acids. To investigate whether this dietary pattern results in high susceptibility of LDL to oxidation, 109 long-term (8 +/- 5 y) male and female vegans and lactovegetarians (ages 31-45 y) from Taipei and females from Hualien and matched omnivores were recruited to have 24-h-recall dietary assessments and blood lipid analysis. Body mass index and blood pressure were significantly lower in all vegetarian groups than in the matched omnivore groups (P < 0.05). Vegetarians consumed less energy except in the males and less protein, fat and cholesterol (P < 0.05). The mean polyunsaturated/saturated fatty acid (P/S) ratio of 2.4 in vegetarian diet was about two times that in omnivore diet (P < 0. 001). The concentrations of plasma total- and LDL-cholesterol (LDL-C) but not HDL-cholesterol (HDL-C) were significantly lower (P < 0.001) and resulting HDL-C/LDL-C ratio was 38, 46 and 30% higher (P < 0.01) in Taipei female, male and Hualien female vegetarians, respectively, than in the matched omnivores. Plasma triglyceride concentration was significantly lower only in the Hualien women vegetarians (31%, P < 0.001) than in the matched omnivores. The lag time of conjugated diene formation in LDL oxidized in vitro induced by copper was longer in Taipei female (62%, P < 0.001), male (29%, P < 0.05) and Hualien female (38%, P < 0.01), and the production of thiobarbituric acid reactive substances (TBARS) in LDL after 2-4 h of oxidation was 22-32% less (P < 0.005) in Taipei male and Hualien female vegetarians than the matched omnivores. Lag time of LDL oxidation was negatively related to LDL arachidonic (r = -0.55, P = 0.0003) and eicosapentaenoic (r = -0.47, P = 0.003) acid contents. LDL-TBARS production was negatively related to LDL linoleic acid content (r = -0.36, P = 0.023), but positively related to LDL arachidonic (r = 0.56, P = 0.0002) and eicosapentaenoic (r = 0.45, P = 0.004) acids. No significant

  12. Facile preparation of heparinized polysulfone membrane assisted by polydopamine/polyethyleneimine co-deposition for simultaneous LDL selectivity and biocompatibility

    NASA Astrophysics Data System (ADS)

    Wang, Liwei; Fang, Fei; Liu, Yang; Li, Jing; Huang, Xiaojun

    2016-11-01

    Low-density lipoprotein (LDL) gains worldwide attention for decades as the key risk factor to atherosclerosis that progressively deteriorating into cardiovascular diseases. Until recent years, LDL-apheresis comes to be extensively used as a direct and efficient LDL removal method, with LDL adsorption materials particularly important. In this paper, a new strategy based on the co-deposition of polydopamine (PDA) with polyethylenimine (PEI) onto polysulfone (PSf) membranes, then subsequent heparinization by amino-carbonyl reactions, to achieve LDL selectivity and simultaneous biocompatibility, is proposed. Surface properties of modified PSf membranes are characterized by ATR-FTIR, XPS, FESEM, Zeta potential and WCA measurements. LDL adsorption ability is investigated by ELISA, while blood biocompatibility is evaluated by platelet adhesion experiments. Results suggest that heparin-modified PSf membranes show high selectivity for LDL removal and fine biocompatibility in contact with plasma, as excellent potential materials for LDL-apheresis.

  13. [Phytosterols: another way to reduce LDL cholesterol levels].

    PubMed

    Bitzur, Rafael; Cohen, Hofit; Kamari, Yehuda; Harats, Dror

    2013-12-01

    Phytosterols are sterols found naturally in various oils from plants. Phytosterols compete with cholesterol for a place in the mixed micelles, needed for cholesterol absorption by the small intestine. As a result, cholesterol absorption, either from food or from bile salts is lowered by about 50%, leading to a towering of about 10% of blood cholesterol level, despite an increase in hepatic cholesterol synthesis. This reduction is achieved when phytosterols are given both as monotherapy, and in addition to statin therapy. The average Western diet contains about 400-800 mg of phytosterols per day, while the dose needed for lowering the blood cholesterol level is about 2-3 grams per day. Therefore, for the purpose of reducing blood cholesterol, they should be given either as phytosterol-enriched food or as supplements. The reduction in the level of LDL-choLesterol achieved with phytosterols may reduce the risk of coronary disease by about 25%. Hence, the American Heart Association recommended the consumption of phytosterols, as part of a balanced diet, for towering blood cholesterol levels.

  14. Decreased training volume and increased carbohydrate intake increases oxidized LDL levels.

    PubMed

    Välimäki, I A; Vuorimaa, T; Ahotupa, M; Kekkonen, R; Korpela, R; Vasankari, T

    2012-04-01

    We studied effects of probiotics and training volume on oxidized LDL lipids (ox-LDL), serum antioxidant potential (s-TRAP) and serum antioxidants (s-α-tocopherol, s-γ-tocopherol, s-retinol, s-β-carotene and s-ubiquinone-10) in marathon runners during 3-months training period, 6-days preparation period and marathon run. Runners (n=127) were recruited for a randomized, double-blind intervention during which they received either Lactobacillus rhamnosus GG (LGG, probiotic group) or placebo drink (placebo group) during whole study. During the preparation period, subjects decreased training and increased carbohydrate intake. Blood samples were taken at baseline, before 6-days preparation, before and immediately after the marathon. Probiotics did not have any effect on ox-LDL, s-TRAP or serum antioxidants levels during the study. Interestingly, ox-LDL increased by 28% and 33% during the preparation period and decreased by 16% and 19% during the marathon run in the placebo and probiotic groups, respectively (in all, P<0.001). No changes were seen in s-TRAP before marathon, but during run s-TRAP raised by 16% in both groups (both, P<0.001). The increase of ox-LDL level during the preparative period after several months' training suggests that aerobic training may reduce the concentration of ox-LDL and that decrease of training together with increased energy intake, mainly carbohydrate, before marathon is capable of increasing the level of ox-LDL.

  15. LDL but not HDL increases adiponectin release of primary human adipocytes.

    PubMed

    Krautbauer, Sabrina; Neumeier, Markus; Eisinger, Kristina; Hader, Yvonne; Dada, Ashraf; Schmitz, Gerd; Aslanidis, Charalampos; Buechler, Christa

    2013-12-01

    Adipocytes in obesity have inappropriately low cholesterol while adiponectin release is reduced. Cholesterol shortage may contribute to low adiponectin and 3T3-L1 cells treated with lovastatin have diminished adiponectin in cell supernatants. LDL and HDL deliver cholesterol to adipocytes. LDL but not HDL increases adiponectin in cell supernatants of primary human adipocytes. The effect of LDL is not blocked by receptor associated protein suggesting that members of the LDL-receptor family are not involved. To evaluate whether these in vitro observations translate into changes in systemic adiponectin, adiponectin was measured in serum of three patients before, immediately after and 3d after LDL-apheresis. Whereas circulating lipoproteins are reduced immediately after apheresis adiponectin is not changed. Therefore, acute lowering of lipoproteins does not affect systemic adiponectin also excluding that plenty of adiponectin is bound to lipoprotein particles. Accordingly, levels of adiponectin in purified lipoproteins are quite low. Familial hypobetalipoproteinemia (FHBL) is a rare disorder associated with low plasma LDL. Serum adiponectin is, however, similar compared to healthy controls. Thus, neither LDL nor HDL directly contributes to circulating adiponectin concentrations.

  16. Naphthalocyanine-reconstituted LDL nanoparticles for in vivo cancer imaging and treatment

    PubMed Central

    Song, Liping; Li, Hui; Sunar, Ulas; Chen, Juan; Corbin, Ian; Yodh, Arjun G; Zheng, Gang

    2007-01-01

    Low density lipoproteins (LDLs) are naturally occurring nanoparticles that are biocompatible, biodegradable and non-immunogenic. Moreover, the size of LDL particle is precisely controlled (~22 nm) by its apoB-100 component, setting them apart from liposomes and lipid micelles. LDL particles have long been proposed as a nanocarrier for targeted delivery of diagnostics and therapeutics to LDL receptor (LDLR)-positive cancers. Here, we report the design and synthesis of a novel naphthalocyanine (Nc)-based photodynamic therapy (PDT) agent, SiNcBOA, and describe its efficient reconstitution into LDL core (100:1 payload). Possessing a near-infrared (NIR) absorption wavelength (>800 nm) and extremely high extinction coefficient (>105 M–1cm–1), SiNcBOA holds the promise of treating deeply seated tumors. Reconstituted LDL particles (r-Nc-LDL) maintain the size and shape of native LDL as determined by transmission electron microscopy, and also retain their LDLR-mediated uptake by cancer cells as demonstrated by confocal microscopy. Its preferential uptake by tumor vs normal tissue was confirmed in vivo by noninvasive optical imaging technique, demonstrating the feasibility of using this nanoparticle for NIR imaging-guided PDT of cancer. PMID:18203443

  17. LDL decreases the membrane compliance and cell adhesion of endothelial cells under fluid shear stress.

    PubMed

    Wei, Dangheng; Chen, Yongpeng; Tang, Chaojun; Huang, Hua; Liu, Lushan; Wang, Zuo; Li, Ruming; Wang, Guixue

    2013-03-01

    Atherosclerosis is an inflammatory disease of large and medium sized arteriole walls that is precipitated by elevated levels of low-density lipoprotein (LDL) cholesterol in the blood. However, the mechanisms that lead to the initiation of atherosclerosis are not fully understood. In this study, endothelial cells (ECs) were incubated with LDL for 24 h, and then the lipid was detected with Oil Red O staining and cholesterol ester was assayed with high-performance liquid chromatography (HPLC). F-actin was examined by fluorescence microscopy and the viscoelasticity of ECs was investigated using the micropipette aspiration technique. Then, a parallel-plate flow chamber device was used to observe the adhesion and retention of ECs under shear stress. The results demonstrated that elevated LDL significantly increased the cellular lipid content and induced the rearrangement of cytoskeletal F-actin. The initial rapid deformability (l/K 1 + l/K 2) was reduced by elevated cellular LDL levels, while membrane viscosity (μ) was increased by LDL accumulation. After treatment with 150 mg L(-1) LDL for 24 h, the adhesion of ECs under fluid shear stress was significantly decreased (p < 0.05). These results suggested that LDL induced cellular lipid accumulation and cytoskeleton reorganization which increased the cellular stiffness and decreased the adhesion of ECs.

  18. LDL acts as an opsonin enhancing the phagocytosis of group A Streptococcus by monocyte and whole human blood.

    PubMed

    Zhou, Lulei; Liu, Ling; Yang, Jinli; Li, Yuxin; Bai, Wencheng; Liu, Na; Li, Wenlong; Gao, Yumin; Xu, Liping; Liu, Zhi; Han, Runlin

    2016-04-01

    Low-density lipoprotein (LDL) binds to group A Streptococcus (GAS) through Sc11 protein, and scavenger receptor CD36 of monocyte mediates the endocytosis of native or modified LDL. Therefore, we hypothesized that LDL might be an opsonin enhancing the phagocytosis of LDL-bound GAS by monocyte. The results showed that LDL could significantly promote U937 cell to phagocytose M28 (ATCC BAA1064) and M41 (ATCC 12373, AM41)-type GAS, and the phagocytosis rates were significantly increased, compared with LDL-free group. LDL, however, did not enhance the phagocytosis of M41 (CMCC 32198, CM41) or M6 (ATCC BAA946)-type GAS since these two strains did not bind to LDL. CD36 was the major scavenger receptor mediating the uptake of LDL-bound GAS by monocyte U937 cells since anti-CD36 antibody abolished the phagocytosis of LDL-opsonized GAS but anti-CD4 antibody did not. Most of AM41-type GAS cells were killed in human blood, whereas only a few CM41-type cells were phagocytosed. Moreover, recombinant Scl1 (rScl1) derived from M41-type GAS could significantly decrease the opsonophagocytosis of AM41 but not CM41-type GAS because the rScl1 competitively blocked the binding of AM41-type GAS to LDL. Therefore, our findings suggest that LDL may be an opsonin to enhance CD36-dependent opsonic phagocytosis of GAS by monocyte.

  19. Proliferation of macrophages due to the inhibition of inducible nitric oxide synthesis by oxidized low-density lipoproteins

    PubMed Central

    Brunner, Monika; Gruber, Miriam; Schmid, Diethart; Baran, Halina; Moeslinger, Thomas

    2015-01-01

    Oxidized low-density lipoprotein (ox-LDL) is assumed to be a major causal agent in hypercholesteraemia-induced atherosclerosis. Because the proliferation of lipid-loaden macrophages within atherosclerotic lesions has been described, we investigated the dependence of macrophage proliferation on the inhibition of inducible nitric oxide synthase (iNOS) by hypochlorite oxidized LDL. Ox-LDL induces a dose dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-interferon stimulated mouse macrophages (J774.A1) with concomitant macrophage proliferation as assayed by cell counting, tritiated-thymidine incorporation and measurement of cell protein. Native LDL did not influence macrophage proliferation and inducible nitric oxide synthesis. iNOS protein and mRNA was reduced by HOCl-oxidized LDL (0-40 µg/ml) as revealed by immunoblotting and competitive semiquantitative PCR. Macrophage proliferation was increased by the addition of the iNOS inhibitor L-NAME. The addition of ox-LDL to L-NAME containing incubations induced no further statistically significant increase in cell number. Nitric oxide donors decreased ox-LDL induced macrophage proliferation and nitric oxide scavengers restored macrophage proliferation to the initial values achieved by ox-LDL. The decrease of cytosolic DNA fragments in stimulated macrophages incubated with ox-LDL demonstrates that the proliferative actions of ox-LDL are associated with a decrease of NO-induced apoptosis. Our data show that inhibition of iNOS dependent nitric oxide production caused by hypochlorite oxidized LDL enhances macrophage proliferation. This might be a key event in the pathogenesis of atherosclerotic lesions. PMID:26600745

  20. SYK regulates macrophage MHC-II expression via activation of autophagy in response to oxidized LDL

    PubMed Central

    Choi, Soo-Ho; Gonen, Ayelet; Diehl, Cody J; Kim, Jungsu; Almazan, Felicidad; Witztum, Joseph L; Miller, Yury I

    2015-01-01

    Adaptive immunity, which plays an important role in the development of atherosclerosis, is mediated by major histocompatibility complex (MHC)-dependent antigen presentation. In atherosclerotic lesions, macrophages constitute an important class of antigen-presenting cells that activate adaptive immune responses to oxidized low-density lipoprotein (OxLDL). It has been reported that autophagy regulates adaptive immune responses by enhancing antigen presentation to MHC class II (MHC-II). In a previous study, we have demonstrated that SYK (spleen tyrosine kinase) regulates generation of reactive oxygen species (ROS) and activation of MAPK8/JNK1 in macrophages. Because ROS and MAPK8 are known to regulate autophagy, in this study we investigated the role of SYK in autophagy, MHC-II expression and adaptive immune response to OxLDL. We demonstrate that OxLDL induces autophagosome formation, MHC-II expression, and phosphorylation of SYK in macrophages. Gene knockout and pharmacological inhibitors of NOX2 and MAPK8 reduced OxLDL-induced autophagy. Using bone marrow-derived macrophages isolated from wild-type and myeloid-specific SYK knockout mice, we demonstrate that SYK regulates OxLDL-induced ROS generation, MAPK8 activation, BECN1-BCL2 dissociation, autophagosome formation and presentation of OxLDL-derived antigens to CD4+ T cells. ldlr−/− syk−/− mice fed a high-fat diet produced lower levels of IgG to malondialdehyde (MDA)-LDL, malondialdehyde-acetaldehyde (MAA)-LDL, and OxLDL compared to ldlr−/− mice. These results provide new insights into the mechanisms by which SYK regulates MHC-II expression via autophagy in macrophages and may contribute to regulation of adaptive immune responses in atherosclerosis. PMID:25946330

  1. CD36 binds oxidized low density lipoprotein (LDL) in a mechanism dependent upon fatty acid binding.

    PubMed

    Jay, Anthony G; Chen, Alexander N; Paz, Miguel A; Hung, Justin P; Hamilton, James A

    2015-02-20

    The association of unesterified fatty acid (FA) with the scavenger receptor CD36 has been actively researched, with focuses on FA and oxidized low density lipoprotein (oxLDL) uptake. CD36 has been shown to bind FA, but this interaction has been poorly characterized to date. To gain new insights into the physiological relevance of binding of FA to CD36, we characterized FA binding to the ectodomain of CD36 by the biophysical method surface plasmon resonance. Five structurally distinct FAs (saturated, monounsaturated (cis and trans), polyunsaturated, and oxidized) were pulsed across surface plasmon resonance channels, generating association and dissociation binding curves. Except for the oxidized FA HODE, all FAs bound to CD36, with rapid association and dissociation kinetics similar to HSA. Next, to elucidate the role that each FA might play in CD36-mediated oxLDL uptake, we used a fluorescent oxLDL (Dii-oxLDL) live cell assay with confocal microscopy imaging. CD36-mediated uptake in serum-free medium was very low but greatly increased when serum was present. The addition of exogenous FA in serum-free medium increased oxLDL binding and uptake to levels found with serum and affected CD36 plasma membrane distribution. Binding/uptake of oxLDL was dependent upon the FA dose, except for docosahexaenoic acid, which exhibited binding to CD36 but did not activate the uptake of oxLDL. HODE also did not affect oxLDL uptake. High affinity FA binding to CD36 and the effects of each FA on oxLDL uptake have important implications for protein conformation, binding of other ligands, functional properties of CD36, and high plasma FA levels in obesity and type 2 diabetes.

  2. On the E-H transition in inductively coupled radio frequency oxygen plasmas: II. Electronegativity and the impact on particle kinetics

    NASA Astrophysics Data System (ADS)

    Wegner, Th; Küllig, C.; Meichsner, J.

    2017-02-01

    In this series of two papers we present results about the E-H transition of an inductively coupled oxygen discharge driven at radio frequency (13.56 MHz) for different total gas pressures. The mode transition from the low density E-mode to the high density H-mode is studied using comprehensive plasma diagnostics. The measured electron density can be used to distinguish between the different operation modes. This paper focuses on the determination of the negative atomic ion density and the electronegativity by two experimental methods and global rate equation calculation. As a result, the electronegativity significantly decreases over two orders of magnitude from about 25 in the E-mode to about 0.1 in the H-mode. The temporal behavior of the electronegativity in pulsed ICP shows that the negative atomic ion density reaches a steady state after 10 ms. Negative atomic ions are mainly produced by the dissociative attachment with the molecular ground state. The ion-ion recombination with the positive molecular ions and the collisional detachment with the singlet molecular metastables contribute significantly to the loss of the negative atomic ions.

  3. Effect of dietary phenolic compounds on apoptosis of human cultured endothelial cells induced by oxidized LDL

    PubMed Central

    Vieira, Otilia; Escargueil-Blanc, Isabelle; Meilhac, Olivier; Basile, Jean-Pierre; Laranjinha, Joao; Almeida, Leonor; Salvayre, Robert; Nègre-Salvayre, Anne

    1998-01-01

    Oxidized low density lipoproteins (LDL) are toxic to cultured endothelial cells. Mildly oxidized LDL, characterized by relatively low levels of TBARS and only minor modifications of apoB, were obtained by using 2 experimental model systems of oxidation, namely oxidation by u.v. radiation or ferrylmyoglobin (a two electron oxidation product from the reaction of metmyoglobin with H2O2). Toxic concentrations of mildly oxidized LDL induce apoptosis (programmed cell death) of cultured endothelial cells, as shown by typical morphological features, by the in situ TUNEL procedure and by DNA fragmentation revealed on gel electrophoresis. This apoptosis is calcium-dependent and subsequent to the intense and sustained cytosolic [Ca2+]i peak elicited by oxidized LDL. Five naturally occurring phenolic compounds present in food and beverages were able to prevent, in a concentration-dependent manner, the apoptosis of endothelial cells induced by oxidized LDL. Among the compounds tested, caffeic acid was the most effective. Under the conditions used, the protective effect of caffeic acid (IC50 8.3±2.1 μmol  l−1) in the prevention of apoptosis induced by oxidized LDL was significantly higher than that of the other compounds tested (IC50s were 12.4±3.2, 14.1±4.1, 20.4±4.4 and 72.6±9.2 μmol  l−1 for ferulic, protocatechuic, ellagic and p-coumaric acids, respectively). The anti-apoptotic effect of caffeic acid results from the addition of two effects, (i) the antioxidant effect which prevents LDL oxidation and subsequent toxicity (‘indirect' protective effect); (ii) a ‘direct' cytoprotective effect, acting at the cellular level. Effective concentrations of caffeic acid acted at the cellular level by blocking the intense and sustained cytosolic [Ca2+]i rise elicited by oxidized LDL. In conclusion, phenolic acids (caffeic and ferulic acids being the most potent of the compounds tested under the conditions used) exhibit a potent cytoprotective effect of

  4. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: a randomized study

    PubMed Central

    Elkan, Ann-Charlotte; Sjöberg, Beatrice; Kolsrud, Björn; Ringertz, Bo; Hafström, Ingiäld; Frostegård, Johan

    2008-01-01

    Introduction The purpose of this study was to investigate the effects of vegan diet in patients with rheumatoid arthritis (RA) on blood lipids oxidized low-density lipoprotein (oxLDL) and natural atheroprotective antibodies against phosphorylcholine (anti-PCs). Methods Sixty-six patients with active RA were randomly assigned to either a vegan diet free of gluten (38 patients) or a well-balanced non-vegan diet (28 patients) for 1 year. Thirty patients in the vegan group completed more than 3 months on the diet regimen. Blood lipids were analyzed by routine methods, and oxLDL and anti-PCs were analyzed by enzyme-linked immunosorbent assay. Data and serum samples were obtained at baseline and after 3 and 12 months. Results Mean ages were 50.0 years for the vegan group and 50.8 years for controls. Gluten-free vegan diet induced lower body mass index (BMI) and low-density lipoprotein (LDL) and higher anti-PC IgM than control diet (p < 0.005). In the vegan group, BMI, LDL, and cholesterol decreased after both 3 and 12 months (p < 0.01) and oxLDL after 3 months (p = 0.021) and trendwise after 12 months (p = 0.090). Triglycerides and high-density lipoprotein did not change. IgA anti-PC levels increased after 3 months (p = 0.027) and IgM anti-PC levels increased trendwise after 12 months (p = 0.057). There was no difference in IgG anti-PC levels. In the control diet group, IgM anti-PC levels decreased both after 3 and 12 months (p < 0.01). When separating vegan patients into clinical responders and non-responders at 12 months, the effects on oxLDL and anti-PC IgA were seen only in responders (p < 0.05). Conclusion A gluten-free vegan diet in RA induces changes that are potentially atheroprotective and anti-inflammatory, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels. PMID:18348715

  5. Inhibitory Effect on In Vitro LDL Oxidation and HMG Co-A Reductase Activity of the Liquid-Liquid Partitioned Fractions of Hericium erinaceus (Bull.) Persoon (Lion's Mane Mushroom)

    PubMed Central

    Aminudin, Norhaniza

    2014-01-01

    Oxidation of low-density lipoprotein (LDL) has been strongly suggested as the key factor in the pathogenesis of atherosclerosis. Mushrooms have been implicated in having preventive effects against chronic diseases due especially to their antioxidant properties. In this study, in vitro inhibitory effect of Hericium erinaceus on LDL oxidation and the activity of the cholesterol biosynthetic key enzyme, 3-hydroxy-3-methyl glutaryl coenzyme A (HMG Co-A) reductase, was evaluated using five liquid-liquid solvent fractions consisting of methanol : dichloromethane (M : DCM), hexane (HEX), dichloromethane (DCM), ethyl acetate (EA), and aqueous residue (AQ). The hexane fraction showed the highest inhibition of oxidation of human LDL as reflected by the increased lag time (100 mins) for the formation of conjugated diene (CD) at 1 µg/mL and decreased production (68.28%, IC50 0.73 mg/mL) of thiobarbituric acid reactive substances (TBARS) at 1 mg/mL. It also mostly inhibited (59.91%) the activity of the HMG Co-A reductase at 10 mg/mL. The GC-MS profiling of the hexane fraction identified the presence of myconutrients: inter alia, ergosterol and linoleic acid. Thus, hexane fraction of Hericium erinaceus was found to be the most potent in vitro inhibitor of both LDL oxidation and HMG Co-A reductase activity having therapeutic potential for the prevention of oxidative stress-mediated vascular diseases. PMID:24959591

  6. Quercetin modulates toll-like receptor-mediated protein kinase signaling pathways in oxLDL-challenged human PBMCs and regulates TLR-activated atherosclerotic inflammation in hypercholesterolemic rats.

    PubMed

    Bhaskar, Shobha; Helen, A

    2016-12-01

    Toll-like receptors (TLRs) are pattern recognition receptors that have a unique and essential function in innate immunity. The effect of quercetin on TLR-mediated downstream signaling mechanism and its effect on TLR-mediated MAP kinase and Akt pathways were studied in oxLDL-stimulated hPBMCs using specific inhibitors. The pretreatment of hPBMCs with specific TLR inhibitor, CLI-095, decreased the NF-κB nuclear translocation and TNF-α release by oxLDL. When the cells treated with inhibitor and quercetin together, the inhibition was more effective. The specific inhibitor for p38 MAPK, SB203580, reduced the phosphorylated p38 level and decreased the NF-κB activation and TNF-α release by oxLDL-challenged hPBMCs. This inhibitor showed enhanced inhibition when treated with quercetin together. The inhibitors for ERK1/2, PD98059, and for JNK, SP606125, also showed inhibitory effect on NF-κB activation and TNF-α release by oxLDL-simulated hPBMCs. Quercetin supplementation enhanced the inhibition of nuclear translocation of NF-κB and the release of cytokines. TLR4 inhibition study confirmed the downstream signaling mechanism mediated by NF-κB which is involved in the oxLDL-induced inflammatory response, and quercetin suppresses the cytokine, TNF-α release by modulating TLR-NF-κB signaling pathway. In addition to NF-κB signaling pathway, inflammation induced by oxLDL was also related to the activation of p38MAPK, ERK1/2 and JNK, and Akt pathways, and the protective effect of quercetin may be also related to the inhibition of activation of these pathways. Quercetin significantly downregulated the elevated mRNA expression of TLRs and cytokine TNF-α in HCD-fed atherosclerotic rats in vivo. As quercetin possesses inhibition on both TLR-NF-κB signaling pathway and TLR-mediated MAPK pathway, it is evident that it can be used as a therapeutic agent to ameliorate atherosclerotic inflammation. Since quercetin is the major flavonoid and forms the backbone of many other

  7. Oxidized low-density lipoprotein (Ox-LDL) impacts on erythrocyte viscoelasticity and its molecular mechanism.

    PubMed

    Wang, Xiang; Yang, Li; Liu, Yao; Gao, Wei; Peng, Weiyan; Sung, K-L Paul; Sung, Lanping Amy

    2009-10-16

    The oxidized low-density lipoprotein (Ox-LDL) plays an important role in atherosclerosis, yet it remains unclear if it damages circulating erythrocytes. In this study, erythrocyte deformability and its membrane proteins after Ox-LDL incubations are investigated by micropipette aspiration, thiol radical measurement, and sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). Results show that Ox-LDL incubation reduces the erythrocyte deformability, decreases free thiol radical contents in erythrocytes, and induces the cross-linking among membrane proteins. SDS-PAGE analysis reveals a high molecular weight (HMW) complex as well as new bands between spectrins and band 3 and reduced ratios between band 3 and other major membrane skeletal proteins. Analyses indicate that Ox-LDL makes erythrocytes harder to deform through a molecular mechanism by which the oxidation of free thiol radicals forms disulfide bonds among membrane skeletal proteins.

  8. A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect

    SciTech Connect

    Landsberger, D.; Meiner, V.; Reshef, A.; Leitersdorf, E. ); Levy, Yishai ); Westhytzen, D.R. van der; Coetzee, G.A. )

    1992-02-01

    Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the LDL receptor gene. Here the authors characterize and LDL receptor mutation that is associated with a distinct haplotype and causes FH in the Druze, a small Middle Eastern Islamic sect with a high degree of inbreeding. The mutation was found in FH families from two distinct Druze villages from the Golan Heights (northern Israel). It was not found either in another Druze FH family residing in a different geographical area nor in eight Arab and four Jewish FH heterozygote index cases whose hypercholesterolemia cosegregates with an identical LDL receptor gene haplotype. The mutation, a single-base substitution, results in a termination codon in exon 4 of the LDL receptor gene that encodes for the fourth repeat of the binding domain of the mature receptor. It can be diagnosed by allele-specific oligonucleotide hybridization of PCR-amplified DNA from FH patients.

  9. Imaging LDL receptor oligomerization during endocytosis using a co-internalization assay

    PubMed Central

    Zou, Peng; Ting, Alice Y.

    2011-01-01

    Methods to probe receptor oligomerization are useful to understand the molecular mechanisms of receptor signaling. Here we report a fluorescence imaging method to determine receptor oligomerization state in living cells during endocytic internalization. The wild-type receptor is co-expressed with an internalization-defective mutant, and the internalization kinetics of each is independently monitored. If the receptor internalizes as an oligomer, then the wild-type and mutant isoforms will mutually influence each others' trafficking properties, causing co-internalization of the mutant, or co-retention of the wild-type at the cell surface. Using this approach, we found that the low density lipoprotein (LDL) receptor internalizes as an oligomer into cells, both in the presence and absence of LDL ligand. The internalization kinetics of the wild-type receptor is not changed by LDL binding. We also found that the oligomerization domain of the LDL receptor is located in its cytoplasmic tail. PMID:21194239

  10. Diet rich in high glucoraphanin broccoli reduces plasma LDL cholesterol: Evidence from randomised controlled trials

    PubMed Central

    Armah, Charlotte N; Derdemezis, Christos; Traka, Maria H; Dainty, Jack R; Doleman, Joanne F; Saha, Shikha; Leung, Wing; Potter, John F; Lovegrove, Julie A; Mithen, Richard F

    2015-01-01

    Scope Cruciferous-rich diets have been associated with reduction in plasma LDL-cholesterol (LDL-C), which may be due to the action of isothiocyanates derived from glucosinolates that accumulate in these vegetables. This study tests the hypothesis that a diet rich in high glucoraphanin (HG) broccoli will reduce plasma LDL-C. Methods and results One hundred and thirty volunteers were recruited to two independent double-blind, randomly allocated parallel dietary intervention studies, and were assigned to consume either 400 g standard broccoli or 400 g HG broccoli per week for 12 weeks. Plasma lipids were quantified before and after the intervention. In study 1 (37 volunteers), the HG broccoli diet reduced plasma LDL-C by 7.1% (95% CI: –1.8%, –12.3%, p = 0.011), whereas standard broccoli reduced LDL-C by 1.8% (95% CI +3.9%, –7.5%, ns). In study 2 (93 volunteers), the HG broccoli diet resulted in a reduction of 5.1% (95% CI: –2.1%, –8.1%, p = 0.001), whereas standard broccoli reduced LDL-C by 2.5% (95% CI: +0.8%, –5.7%, ns). When data from the two studies were combined the reduction in LDL-C by the HG broccoli was significantly greater than standard broccoli (p = 0.031). Conclusion Evidence from two independent human studies indicates that consumption of high glucoraphanin broccoli significantly reduces plasma LDL-C. PMID:25851421

  11. ATVB Council Statement: Non-statin LDL-lowering Therapy and Cardiovascular Risk Reduction

    PubMed Central

    Hegele, Robert A.; Gidding, Samuel S.; Ginsberg, Henry N.; McPherson, Ruth; Raal, Frederick J.; Rader, Daniel J.; Robinson, Jennifer G.; Welty, Francine K.

    2015-01-01

    Pharmacologic reduction of low-density lipoprotein (LDL) cholesterol using statin drugs is foundational therapy to reduce cardiovascular disease (CVD) risk. Here we consider the place of non-statin therapies that also reduce LDL cholesterol in prevention of CVD. Among conventional non-statins, placebo-controlled randomized clinical trials showed that bile acid sequestrants, niacin and fibrates given as monotherapy each reduce CVD end points. From trials in which patients’ LDL cholesterol was already well-controlled on a statin, adding ezetimibe incrementally reduced CVD end points, while adding a fibrate or niacin showed no incremental benefit. Among emerging non-statins, monoclonal antibodies against proprotein convertase subtilisin kexin type 9 (PCSK9) added to a statin and given for up to 78 weeks showed preliminary evidence of reductions in CVD outcomes. While these promising early findings contributed to the recent approval of these agents in Europe and the US, much larger and longer duration outcomes studies are ongoing for definitive proof of CVD benefits. Other non-statin agents recently approved in the US include lomitapide and mipomersen, which both act via distinctive LDL-receptor independent mechanisms to substantially reduce LDL cholesterol in homozygous familial hypercholesterolemia. We also address some unanswered questions, including measuring alternative biochemical variables to LDL cholesterol, evidence for treating children with monitoring of subclinical atherosclerosis, and potential risks of extremely low LDL cholesterol. As evidence for benefit in CVD prevention accumulates, we anticipate that clinical practice will shift towards more assertive LDL-lowering treatment, using both statins and non-statins initiated earlier in appropriately selected patients. PMID:26376908

  12. Native LDL promotes differentiation of human monocytes to macrophages with an inflammatory phenotype.

    PubMed

    Al-Sharea, Annas; Lee, Man Kit Sam; Moore, Xiao-Lei; Fang, Lu; Sviridov, Dmitri; Chin-Dusting, Jaye; Andrews, Karen L; Murphy, Andrew J

    2016-04-01

    Recruitment of monocytes in atherosclerosis is dependent upon increased levels of plasma lipoproteins which accumulate in the blood vessel wall. The extracellular milieu can influence the phenotype of monocyte subsets (classical: CD14++CD16-, intermediate: CD14+CD16+ and non-classical: CD14dimCD16++) and macrophages (M1 or M2) and consequently the initiation, progression and/or regression of atherosclerosis. However, it is not known what effect lipoproteins, in particular native low-density lipoproteins (nLDL), have on the polarisation of monocyte-derived macrophages. Monocytes were differentiated into macrophages in the presence of nLDL. nLDL increased gene expression of the inflammatory cytokines TNFα and IL-6 in macrophages polarised towards the M1 phenotype while decreasing the M2 surface markers, CD206 and CD200R and the anti-inflammatory cytokines TGFβ and IL-10. Compared to the classical and intermediate subsets, the non-classical subset-derived macrophages had a reduced ability to respond to M1 stimuli (LPS and IFNγ). nLDL enhanced the TNFα and IL-6 gene expression in macrophages from all monocyte subsets, indicating an inflammatory effect of nLDL. Further, the classical and intermediate subsets both responded to M2 stimuli (IL-4) with upregulation of TGFβ and SR-B1 mRNA; an effect, which was reduced by nLDL. In contrast, the non-classical subset failed to respond to IL-4 or nLDL, suggesting it may be unable to polarise into M2 macrophages. Our data suggests that monocyte interaction with nLDL significantly affects macrophage polarisation and that this interaction appears to be subset dependent.

  13. The LDL-HDL Profile Determines the Risk of Atherosclerosis: A Mathematical Model

    PubMed Central

    Hao, Wenrui; Friedman, Avner

    2014-01-01

    Atherosclerosis, the leading death in the United State, is a disease in which a plaque builds up inside the arteries. As the plaque continues to grow, the shear force of the blood flow through the decreasing cross section of the lumen increases. This force may eventually cause rupture of the plaque, resulting in the formation of thrombus, and possibly heart attack. It has long been recognized that the formation of a plaque relates to the cholesterol concentration in the blood. For example, individuals with LDL above 190 mg/dL and HDL below 40 mg/dL are at high risk, while individuals with LDL below 100 mg/dL and HDL above 50 mg/dL are at no risk. In this paper, we developed a mathematical model of the formation of a plaque, which includes the following key variables: LDL and HDL, free radicals and oxidized LDL, MMP and TIMP, cytockines: MCP-1, IFN-γ, IL-12 and PDGF, and cells: macrophages, foam cells, T cells and smooth muscle cells. The model is given by a system of partial differential equations with in evolving plaque. Simulations of the model show how the combination of the concentrations of LDL and HDL in the blood determine whether a plaque will grow or disappear. More precisely, we create a map, showing the risk of plaque development for any pair of values (LDL,HDL). PMID:24621857

  14. The LDL-HDL profile determines the risk of atherosclerosis: a mathematical model.

    PubMed

    Hao, Wenrui; Friedman, Avner

    2014-01-01

    Atherosclerosis, the leading death in the United State, is a disease in which a plaque builds up inside the arteries. As the plaque continues to grow, the shear force of the blood flow through the decreasing cross section of the lumen increases. This force may eventually cause rupture of the plaque, resulting in the formation of thrombus, and possibly heart attack. It has long been recognized that the formation of a plaque relates to the cholesterol concentration in the blood. For example, individuals with LDL above 190 mg/dL and HDL below 40 mg/dL are at high risk, while individuals with LDL below 100 mg/dL and HDL above 50 mg/dL are at no risk. In this paper, we developed a mathematical model of the formation of a plaque, which includes the following key variables: LDL and HDL, free radicals and oxidized LDL, MMP and TIMP, cytockines: MCP-1, IFN-γ, IL-12 and PDGF, and cells: macrophages, foam cells, T cells and smooth muscle cells. The model is given by a system of partial differential equations with in evolving plaque. Simulations of the model show how the combination of the concentrations of LDL and HDL in the blood determine whether a plaque will grow or disappear. More precisely, we create a map, showing the risk of plaque development for any pair of values (LDL,HDL).

  15. The glycosylation-dependent interaction of perlecan core protein with LDL: implications for atherosclerosis[S

    PubMed Central

    Xu, Yu-Xin; Ashline, David; Liu, Li; Tassa, Carlos; Shaw, Stanley Y.; Ravid, Katya; Layne, Matthew D.; Reinhold, Vernon; Robbins, Phillips W.

    2015-01-01

    Perlecan is a major heparan sulfate (HS) proteoglycan in the arterial wall. Previous studies have linked it to atherosclerosis. Perlecan contains a core protein and three HS side chains. Its core protein has five domains (DI–DV) with disparate structures and DII is highly homologous to the ligand-binding portion of LDL receptor (LDLR). The functional significance of this domain has been unknown. Here, we show that perlecan DII interacts with LDL. Importantly, the interaction largely relies on O-linked glycans that are only present in the secreted DII. Among the five repeat units of DII, most of the glycosylation sites are from the second unit, which is highly divergent and rich in serine and threonine, but has no cysteine residues. Interestingly, most of the glycans are capped by the negatively charged sialic acids, which are critical for LDL binding. We further demonstrate an additive effect of HS and DII on LDL binding. Unlike LDLR, which directs LDL uptake through endocytosis, this study uncovers a novel feature of the perlecan LDLR-like DII in receptor-mediated lipoprotein retention, which depends on its glycosylation. Thus, perlecan glycosylation may play a role in the early LDL retention during the development of atherosclerosis. PMID:25528754

  16. Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol

    PubMed Central

    Lange, Leslie A.; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M.; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M.; Smith, Joshua D.; Turner, Emily H.; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A.; Holmen, Oddgeir L.; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A.; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C.; Correa, Adolfo; Griswold, Michael E.; Jakobsdottir, Johanna; Smith, Albert V.; Schreiner, Pamela J.; Feitosa, Mary F.; Zhang, Qunyuan; Huffman, Jennifer E.; Crosby, Jacy; Wassel, Christina L.; Do, Ron; Franceschini, Nora; Martin, Lisa W.; Robinson, Jennifer G.; Assimes, Themistocles L.; Crosslin, David R.; Rosenthal, Elisabeth A.; Tsai, Michael; Rieder, Mark J.; Farlow, Deborah N.; Folsom, Aaron R.; Lumley, Thomas; Fox, Ervin R.; Carlson, Christopher S.; Peters, Ulrike; Jackson, Rebecca D.; van Duijn, Cornelia M.; Uitterlinden, André G.; Levy, Daniel; Rotter, Jerome I.; Taylor, Herman A.; Gudnason, Vilmundur; Siscovick, David S.; Fornage, Myriam; Borecki, Ingrid B.; Hayward, Caroline; Rudan, Igor; Chen, Y. Eugene; Bottinger, Erwin P.; Loos, Ruth J.F.; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M.; Gabriel, Stacey B.; O’Donnell, Christopher J.; Post, Wendy S.; North, Kari E.; Reiner, Alexander P.; Boerwinkle, Eric; Psaty, Bruce M.; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P.; Cupples, L. Adrienne; Kooperberg, Charles; Wilson, James G.; Nickerson, Deborah A.; Abecasis, Goncalo R.; Rich, Stephen S.; Tracy, Russell P.; Willer, Cristen J.; Gabriel, Stacey B.; Altshuler, David M.; Abecasis, Gonçalo R.; Allayee, Hooman; Cresci, Sharon; Daly, Mark J.; de Bakker, Paul I.W.; DePristo, Mark A.; Do, Ron; Donnelly, Peter; Farlow, Deborah N.; Fennell, Tim; Garimella, Kiran; Hazen, Stanley L.; Hu, Youna; Jordan, Daniel M.; Jun, Goo; Kathiresan, Sekar; Kang, Hyun Min; Kiezun, Adam; Lettre, Guillaume; Li, Bingshan; Li, Mingyao; Newton-Cheh, Christopher H.; Padmanabhan, Sandosh; Peloso, Gina; Pulit, Sara; Rader, Daniel J.; Reich, David; Reilly, Muredach P.; Rivas, Manuel A.; Schwartz, Steve; Scott, Laura; Siscovick, David S.; Spertus, John A.; Stitziel, Nathaniel O.; Stoletzki, Nina; Sunyaev, Shamil R.; Voight, Benjamin F.; Willer, Cristen J.; Rich, Stephen S.; Akylbekova, Ermeg; Atwood, Larry D.; Ballantyne, Christie M.; Barbalic, Maja; Barr, R. Graham; Benjamin, Emelia J.; Bis, Joshua; Boerwinkle, Eric; Bowden, Donald W.; Brody, Jennifer; Budoff, Matthew; Burke, Greg; Buxbaum, Sarah; Carr, Jeff; Chen, Donna T.; Chen, Ida Y.; Chen, Wei-Min; Concannon, Pat; Crosby, Jacy; Cupples, L. Adrienne; D’Agostino, Ralph; DeStefano, Anita L.; Dreisbach, Albert; Dupuis, Josée; Durda, J. Peter; Ellis, Jaclyn; Folsom, Aaron R.; Fornage, Myriam; Fox, Caroline S.; Fox, Ervin; Funari, Vincent; Ganesh, Santhi K.; Gardin, Julius; Goff, David; Gordon, Ora; Grody, Wayne; Gross, Myron; Guo, Xiuqing; Hall, Ira M.; Heard-Costa, Nancy L.; Heckbert, Susan R.; Heintz, Nicholas; Herrington, David M.; Hickson, DeMarc; Huang, Jie; Hwang, Shih-Jen; Jacobs, David R.; Jenny, Nancy S.; Johnson, Andrew D.; Johnson, Craig W.; Kawut, Steven; Kronmal, Richard; Kurz, Raluca; Lange, Ethan M.; Lange, Leslie A.; Larson, Martin G.; Lawson, Mark; Lewis, Cora E.; Levy, Daniel; Li, Dalin; Lin, Honghuang; Liu, Chunyu; Liu, Jiankang; Liu, Kiang; Liu, Xiaoming; Liu, Yongmei; Longstreth, William T.; Loria, Cay; Lumley, Thomas; Lunetta, Kathryn; Mackey, Aaron J.; Mackey, Rachel; Manichaikul, Ani; Maxwell, Taylor; McKnight, Barbara; Meigs, James B.; Morrison, Alanna C.; Musani, Solomon K.; Mychaleckyj, Josyf C.; Nettleton, Jennifer A.; North, Kari; O’Donnell, Christopher J.; O’Leary, Daniel; Ong, Frank; Palmas, Walter; Pankow, James S.; Pankratz, Nathan D.; Paul, Shom; Perez, Marco; Person, Sharina D.; Polak, Joseph; Post, Wendy S.; Psaty, Bruce M.; Quinlan, Aaron R.; Raffel, Leslie J.; Ramachandran, Vasan S.; Reiner, Alexander P.; Rice, Kenneth; Rotter, Jerome I.; Sanders, Jill P.; Schreiner, Pamela; Seshadri, Sudha; Shea, Steve; Sidney, Stephen; Silverstein, Kevin; Smith, Nicholas L.; Sotoodehnia, Nona; Srinivasan, Asoke; Taylor, Herman A.; Taylor, Kent; Thomas, Fridtjof; Tracy, Russell P.; Tsai, Michael Y.; Volcik, Kelly A.; Wassel, Chrstina L.; Watson, Karol; Wei, Gina; White, Wendy; Wiggins, Kerri L.; Wilk, Jemma B.; Williams, O. Dale; Wilson, Gregory; Wilson, James G.; Wolf, Phillip; Zakai, Neil A.; Hardy, John; Meschia, James F.; Nalls, Michael; Singleton, Andrew; Worrall, Brad; Bamshad, Michael J.; Barnes, Kathleen C.; Abdulhamid, Ibrahim; Accurso, Frank; Anbar, Ran; Beaty, Terri; Bigham, Abigail; Black, Phillip; Bleecker, Eugene; Buckingham, Kati; Cairns, Anne Marie; Caplan, Daniel; Chatfield, Barbara; Chidekel, Aaron; Cho, Michael; Christiani, David C.; Crapo, James D.; Crouch, Julia; Daley, Denise; Dang, Anthony; Dang, Hong; De Paula, Alicia; DeCelie-Germana, Joan; Drumm, Allen DozorMitch; Dyson, Maynard; Emerson, Julia; Emond, Mary J.; Ferkol, Thomas; Fink, Robert; Foster, Cassandra; Froh, Deborah; Gao, Li; Gershan, William; Gibson, Ronald L.; Godwin, Elizabeth; Gondor, Magdalen; Gutierrez, Hector; Hansel, Nadia N.; Hassoun, Paul M.; Hiatt, Peter; Hokanson, John E.; Howenstine, Michelle; Hummer, Laura K.; Kanga, Jamshed; Kim, Yoonhee; Knowles, Michael R.; Konstan, Michael; Lahiri, Thomas; Laird, Nan; Lange, Christoph; Lin, Lin; Lin, Xihong; Louie, Tin L.; Lynch, David; Make, Barry; Martin, Thomas R.; Mathai, Steve C.; Mathias, Rasika A.; McNamara, John; McNamara, Sharon; Meyers, Deborah; Millard, Susan; Mogayzel, Peter; Moss, Richard; Murray, Tanda; Nielson, Dennis; Noyes, Blakeslee; O’Neal, Wanda; Orenstein, David; O’Sullivan, Brian; Pace, Rhonda; Pare, Peter; Parker, H. Worth; Passero, Mary Ann; Perkett, Elizabeth; Prestridge, Adrienne; Rafaels, Nicholas M.; Ramsey, Bonnie; Regan, Elizabeth; Ren, Clement; Retsch-Bogart, George; Rock, Michael; Rosen, Antony; Rosenfeld, Margaret; Ruczinski, Ingo; Sanford, Andrew; Schaeffer, David; Sell, Cindy; Sheehan, Daniel; Silverman, Edwin K.; Sin, Don; Spencer, Terry; Stonebraker, Jackie; Tabor, Holly K.; Varlotta, Laurie; Vergara, Candelaria I.; Weiss, Robert; Wigley, Fred; Wise, Robert A.; Wright, Fred A.; Wurfel, Mark M.; Zanni, Robert; Zou, Fei; Nickerson, Deborah A.; Rieder, Mark J.; Green, Phil; Shendure, Jay; Akey, Joshua M.; Bustamante, Carlos D.; Crosslin, David R.; Eichler, Evan E.; Fox, P. Keolu; Fu, Wenqing; Gordon, Adam; Gravel, Simon; Jarvik, Gail P.; Johnsen, Jill M.; Kan, Mengyuan; Kenny, Eimear E.; Kidd, Jeffrey M.; Lara-Garduno, Fremiet; Leal, Suzanne M.; Liu, Dajiang J.; McGee, Sean; O’Connor, Timothy D.; Paeper, Bryan; Robertson, Peggy D.; Smith, Joshua D.; Staples, Jeffrey C.; Tennessen, Jacob A.; Turner, Emily H.; Wang, Gao; Yi, Qian; Jackson, Rebecca; Peters, Ulrike; Carlson, Christopher S.; Anderson, Garnet; Anton-Culver, Hoda; Assimes, Themistocles L.; Auer, Paul L.; Beresford, Shirley; Bizon, Chris; Black, Henry; Brunner, Robert; Brzyski, Robert; Burwen, Dale; Caan, Bette; Carty, Cara L.; Chlebowski, Rowan; Cummings, Steven; Curb, J. David; Eaton, Charles B.; Ford, Leslie; Franceschini, Nora; Fullerton, Stephanie M.; Gass, Margery; Geller, Nancy; Heiss, Gerardo; Howard, Barbara V.; Hsu, Li; Hutter, Carolyn M.; Ioannidis, John; Jiao, Shuo; Johnson, Karen C.; Kooperberg, Charles; Kuller, Lewis; LaCroix, Andrea; Lakshminarayan, Kamakshi; Lane, Dorothy; Lasser, Norman; LeBlanc, Erin; Li, Kuo-Ping; Limacher, Marian; Lin, Dan-Yu; Logsdon, Benjamin A.; Ludlam, Shari; Manson, JoAnn E.; Margolis, Karen; Martin, Lisa; McGowan, Joan; Monda, Keri L.; Kotchen, Jane Morley; Nathan, Lauren; Ockene, Judith; O’Sullivan, Mary Jo; Phillips, Lawrence S.; Prentice, Ross L.; Robbins, John; Robinson, Jennifer G.; Rossouw, Jacques E.; Sangi-Haghpeykar, Haleh; Sarto, Gloria E.; Shumaker, Sally; Simon, Michael S.; Stefanick, Marcia L.; Stein, Evan; Tang, Hua; Taylor, Kira C.; Thomson, Cynthia A.; Thornton, Timothy A.; Van Horn, Linda; Vitolins, Mara; Wactawski-Wende, Jean; Wallace, Robert; Wassertheil-Smoller, Sylvia; Zeng, Donglin; Applebaum-Bowden, Deborah; Feolo, Michael; Gan, Weiniu; Paltoo, Dina N.; Sholinsky, Phyliss; Sturcke, Anne

    2014-01-01

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98th or <2nd percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments. PMID:24507775

  17. Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol.

    PubMed

    Lange, Leslie A; Hu, Youna; Zhang, He; Xue, Chenyi; Schmidt, Ellen M; Tang, Zheng-Zheng; Bizon, Chris; Lange, Ethan M; Smith, Joshua D; Turner, Emily H; Jun, Goo; Kang, Hyun Min; Peloso, Gina; Auer, Paul; Li, Kuo-Ping; Flannick, Jason; Zhang, Ji; Fuchsberger, Christian; Gaulton, Kyle; Lindgren, Cecilia; Locke, Adam; Manning, Alisa; Sim, Xueling; Rivas, Manuel A; Holmen, Oddgeir L; Gottesman, Omri; Lu, Yingchang; Ruderfer, Douglas; Stahl, Eli A; Duan, Qing; Li, Yun; Durda, Peter; Jiao, Shuo; Isaacs, Aaron; Hofman, Albert; Bis, Joshua C; Correa, Adolfo; Griswold, Michael E; Jakobsdottir, Johanna; Smith, Albert V; Schreiner, Pamela J; Feitosa, Mary F; Zhang, Qunyuan; Huffman, Jennifer E; Crosby, Jacy; Wassel, Christina L; Do, Ron; Franceschini, Nora; Martin, Lisa W; Robinson, Jennifer G; Assimes, Themistocles L; Crosslin, David R; Rosenthal, Elisabeth A; Tsai, Michael; Rieder, Mark J; Farlow, Deborah N; Folsom, Aaron R; Lumley, Thomas; Fox, Ervin R; Carlson, Christopher S; Peters, Ulrike; Jackson, Rebecca D; van Duijn, Cornelia M; Uitterlinden, André G; Levy, Daniel; Rotter, Jerome I; Taylor, Herman A; Gudnason, Vilmundur; Siscovick, David S; Fornage, Myriam; Borecki, Ingrid B; Hayward, Caroline; Rudan, Igor; Chen, Y Eugene; Bottinger, Erwin P; Loos, Ruth J F; Sætrom, Pål; Hveem, Kristian; Boehnke, Michael; Groop, Leif; McCarthy, Mark; Meitinger, Thomas; Ballantyne, Christie M; Gabriel, Stacey B; O'Donnell, Christopher J; Post, Wendy S; North, Kari E; Reiner, Alexander P; Boerwinkle, Eric; Psaty, Bruce M; Altshuler, David; Kathiresan, Sekar; Lin, Dan-Yu; Jarvik, Gail P; Cupples, L Adrienne; Kooperberg, Charles; Wilson, James G; Nickerson, Deborah A; Abecasis, Goncalo R; Rich, Stephen S; Tracy, Russell P; Willer, Cristen J

    2014-02-06

    Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

  18. Study of the electron kinetic processes in laser-induced breakdown of electronegative gases over an extended wavelength range

    NASA Astrophysics Data System (ADS)

    Gamal, Yosr E. E.-D.; Omar, M. M.

    2001-12-01

    A theoretical investigation of laser-induced breakdown of electronegative gases is presented. The formulations are based on an electron cascade model previously developed by Evans and Gamal (J. Phys. D: Appl. Phys. 13 (1980) 1447-1458). This model solves numerically the time-dependent Boltzmann equation simultaneously with a set of rate equations describing the population density of the formed excited states. It includes the possible kinds of interactions between electrons, molecules and photons. Calculations are carried out under the experimental conditions of Davis et al. (Appl. Optics 30 (1991) 4358-4364) where molecular oxygen over a pressure range of 20-760 Torr is irradiated with the first four harmonics of a Nd : YAG laser source at wavelengths 1064, 532, 355 and 266 nm of pulse duration 8.5, 7.5, 6.5 and 5.5 ns, respectively, and peak irradiance varies between 3.6×10 10 and 3.7×10 11 W/cm 2. Computations revealed that the dependence of threshold irradiance on gas pressure is in quite close agreement with those measured by Davis et al. (1991) for the four laser wavelengths considered in this analysis. It is also shown that at laser wavelengths 532 and 266 nm oxygen breakdown is mainly governed by the combined effect of two and three-body attachment loss processes, while for the wavelengths 335and 1064 nm, the three-body attachment process dominates. In addition, calculation of the electron energy distribution function and its parameters, viz, electron density, ionization rate and electron mean energy predicted the importance of the photoionization of excited states as the main electron generation process over the short wavelength range.

  19. Experimental validation of the dual positive and negative ion beam acceleration in the plasma propulsion with electronegative gases thruster

    SciTech Connect

    Rafalskyi, Dmytro Popelier, Lara; Aanesland, Ane

    2014-02-07

    The PEGASES (Plasma Propulsion with Electronegative Gases) thruster is a gridded ion thruster, where both positive and negative ions are accelerated to generate thrust. In this way, additional downstream neutralization by electrons is redundant. To achieve this, the thruster accelerates alternately positive and negative ions from an ion-ion plasma where the electron density is three orders of magnitude lower than the ion densities. This paper presents a first experimental study of the alternate acceleration in PEGASES, where SF{sub 6} is used as the working gas. Various electrostatic probes are used to investigate the source plasma potential and the energy, composition, and current of the extracted beams. We show here that the plasma potential control in such system is key parameter defining success of ion extraction and is sensitive to both parasitic electron current paths in the source region and deposition of sulphur containing dielectric films on the grids. In addition, large oscillations in the ion-ion plasma potential are found in the negative ion extraction phase. The oscillation occurs when the primary plasma approaches the grounded parts of the main core via sub-millimetres technological inputs. By controlling and suppressing the various undesired effects, we achieve perfect ion-ion plasma potential control with stable oscillation-free operation in the range of the available acceleration voltages (±350 V). The measured positive and negative ion currents in the beam are about 10 mA for each component at RF power of 100 W and non-optimized extraction system. Two different energy analyzers with and without magnetic electron suppression system are used to measure and compare the negative and positive ion and electron fluxes formed by the thruster. It is found that at alternate ion-ion extraction the positive and negative ion energy peaks are similar in areas and symmetrical in position with +/− ion energy corresponding to the amplitude of the applied

  20. Simvastatin Efficiently Lowers Small LDL-IgG Immune Complex Levels: A Therapeutic Quality beyond the Lipid-Lowering Effect

    PubMed Central

    Ferstl, Ulrika; Ledinski, Gerhard; Binder, Josepha; Cvirn, Gerhard; Stojakovic, Tatjana; Trauner, Michael; Koidl, Christoph; Tafeit, Erwin; Amrein, Karin; Scharnagl, Hubert; Jürgens, Günther; Hallström, Seth

    2016-01-01

    We investigated a polyethylene glycol non-precipitable low-density lipoprotein (LDL) subfraction targeted by IgG and the influence of statin therapy on plasma levels of these small LDL-IgG-immune complexes (LDL-IgG-IC). LDL-subfractions were isolated from 6 atherosclerotic subjects and 3 healthy individuals utilizing iodixanol density gradient ultracentrifugation. Cholesterol, apoB and malondialdehyde (MDA) levels were determined in each fraction by enzymatic testing, dissociation-enhanced lanthanide fluorescence immunoassay and high-performance liquid chromatography, respectively. The levels of LDL-IgG-IC were quantified densitometrically following lipid electrophoresis, particle size distribution was assessed with dynamic light scattering and size exclusion chromatography. The influence of simvastatin (40 mg/day for three months) on small LDL-IgG-IC levels and their distribution among LDL-subfractions (salt gradient separation) were investigated in 11 patients with confirmed coronary artery disease (CAD). We demonstrate that the investigated LDL-IgG-IC are small particles present in atherosclerotic patients and healthy subjects. In vitro assembly of LDL-IgG-IC resulted in particle density shifts indicating a composition of one single molecule of IgG per LDL particle. Normalization on cholesterol levels revealed MDA values twice as high for LDL-subfractions rich in small LDL-IgG-IC if compared to dominant LDL-subfractions. Reactivity of affinity purified small LDL-IgG-IC to monoclonal antibody OB/04 indicates a high degree of modified apoB and oxidative modification. Simvastatin therapy studied in the CAD patients significantly lowered LDL levels and to an even higher extent, small LDL-IgG-IC levels without affecting their distribution. In conclusion simvastatin lowers levels of small LDL-IgG-IC more effectively than LDL-cholesterol and LDL-apoB levels in atherosclerotic patients. This antiatherogenic effect may additionally contribute to the known beneficial

  1. Protective activity of plicatin B against human LDL oxidation induced in metal ion-dependent and -independent processes. Experimental and theoretical studies.

    PubMed

    Turchi, G; Alagona, G; Lubrano, V

    2009-11-01

    Oxidation of low-density lipoproteins (LDL) is thought to be a major factor in the pathophysiology of atherosclerosis. Natural antioxidants have been shown to protect LDL from oxidation and to inhibit atherogenic developments in animals. Structurally related prenylated pterocarpans, erybraedin C and bitucarpin A, and the prenylchalcone plicatin B were examined for their ability to inhibit LDL oxidation in vitro. The kinetic profile of peroxidation is characterized by the lag time of oxidation (t(lag)), the maximal rate of oxidation (V(max)) and the maximal accumulation of oxidation products (OD(max)). Specific variation of the set of kinetic parameters by antioxidants may provide important information about the mechanism of inhibitory action of a given compound. At equimolar concentrations (1 microM) the prenylated derivatives tested were found to inhibit 1 microM copper sulphate-induced oxidation of LDL (50 microg protein/ml) in accordance with the following order of activity: plicatin B>erybraedin Cbitucarpin A. Structural aspects, such as hydrogen-donating substituents, their number and arrangement in the aromatic ring moieties, and the prenyl and methoxy substituents, were investigated in order to explain the findings obtained. It is well known that the antioxidant activity of flavonoids is believed to be caused by a combination of transition metal chelation and free-radical-scavenging activities. To investigate these differences we comparatively studied the protective mechanism of plicatin B in copper-dependent or -independent LDL oxidation. The latter was mediated by 2,2'-azo-bis-(2-amidinopropane) dihydrochloride (ABAP). We measured the formation of conjugated dienes (OD(234 nm)). Plicatin B (0.2-1.5 microM) delayed the Cu(2+) (1 microM) promoted oxidation as conjugate diene formation (t(lag)) of the LDL by 45.2-123.5 min and reduced V(max) by 0.46-0.29 microM/min. In the ABAP (0.2mM) promoted LDL oxidation t(lag) increased by 67.2-110.2 min through plicatin

  2. TLR4/NF-κB signaling pathway-mediated and oxLDL-induced up-regulation of LOX-1, MCP-1, and VCAM-1 expressions in human umbilical vein endothelial cells.

    PubMed

    Feng, Y; Cai, Z R; Tang, Y; Hu, G; Lu, J; He, D; Wang, S

    2014-01-28

    This study aimed to investigate the function and signaling pathway of Toll-like receptor 4 (TLR4) in oxidized low-density lipoprotein (oxLDL)-induced up-regulated expressions of oxidized LDL receptor 1 (LOX-1), monocyte chemoattractant protein 1 (MCP-1), and vascular cell adhesion molecule 1 (VCAM-1) in human umbilical vein endothelial cells (HUVECs). HUVECs were incubated with different oxLDL concentrations (0, 20, 40, 60, and 80 μg/mL) for 24 and 48 h. The influence of oxLDL on TLR4, LOX-1, MCP-1, and VCAM-1 expressions in HUVECs was detected by real-time polymerase chain reaction and Western blot analysis. HUVECs were transfected with small interfering RNA targeting TLR4 (siTLR4), in which protein expressions of LOX-1, MCP-1, and VCAM-1, and the nuclear translocation of NF-kB (P50) were detected by Western blot. After 48 h of processing HUVECs with pyrrolidine dithiocarbamate (PDTC), protein expressions of TLR4, LOX-1, MCP-1, and VCAM- 1 were detected by Western blot. OxLDL induced a concentration-dependent up-regulation of mRNA and protein expressions of TLR4, LOX-1, MCP-1, and VCAM-1 in HUVECs (P < 0.001). siTLR4 significantly reduced protein expressions of LOX-1, MCP-1, VCAM-1, and reduced the NF-kB (P50) nuclear translocation (P < 0.001). PDTC significantly inhibited protein expressions of TLR4, LOX-1, MCP- 1, and VCAM-1 (P < 0.001). Results of this study demonstrate that the TLR4/NF-κB signaling pathway has an important function in the up-regulation of oxLDL-induced expressions of LOX-1, MCP-1, and VCAM-1 in HUVECs.

  3. A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s.

    PubMed

    Calabuig-Navarro, M V; Jackson, K G; Kemp, C F; Leake, D S; Walden, C M; Lovegrove, J A; Minihane, A M

    2017-03-09

    At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4-6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482.

  4. A randomized trial and novel SPR technique identifies altered lipoprotein-LDL receptor binding as a mechanism underlying elevated LDL-cholesterol in APOE4s

    PubMed Central

    Calabuig-Navarro, M. V.; Jackson, K. G.; Kemp, C. F.; Leake, D. S.; Walden, C. M.; Lovegrove, J. A.; Minihane, A. M.

    2017-01-01

    At a population level APOE4 carriers (~25% Caucasians) are at higher risk of cardiovascular diseases. The penetrance of genotype is however variable and influenced by dietary fat composition, with the APOE4 allele associated with greater LDL-cholesterol elevation in response to saturated fatty acids (SFA). The etiology of this greater responsiveness is unknown. Here a novel surface plasmon resonance technique (SPR) is developed and used, along with hepatocyte (with the liver being the main organ modulating lipoprotein metabolism and plasma lipid levels) uptake studies to establish the impact of dietary fatty acid composition on, lipoprotein-LDL receptor (LDLR) binding, and hepatocyte uptake, according to APOE genotype status. In men prospectively recruited according to APOE genotype (APOE3/3 common genotype, or APOE3/E4), triglyceride-rich lipoproteins (TRLs) were isolated at fasting and 4–6 h following test meals rich in SFA, unsaturated fat and SFA with fish oil. In APOE4s a greater LDLR binding affinity of postprandial TRL after SFA, and lower LDL binding and hepatocyte internalization, provide mechanisms for the greater LDL-cholesterol raising effect. The SPR technique developed may be used for the future study of the impact of genotype, and physiological and behavioral variables on lipoprotein metabolism. Trial registration number NCT01522482. PMID:28276521

  5. An olive oil-rich diet results in higher concentrations of LDL cholesterol and a higher number of LDL subfraction particles than rapeseed oil and sunflower oil diets.

    PubMed

    Pedersen, A; Baumstark, M W; Marckmann, P; Gylling, H; Sandström, B

    2000-12-01

    We investigated the effect of olive oil, rapeseed oil, and sunflower oil on blood lipids and lipoproteins including number and lipid composition of lipoprotein subclasses. Eighteen young, healthy men participated in a double-blinded randomized cross-over study (3-week intervention period) with 50 g of oil per 10 MJ incorporated into a constant diet. Plasma cholesterol, triacylglycerol, apolipoprotein B, and very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) cholesterol concentrations were 10;-20% higher after consumption of the olive oil diet compared with the rapeseed oil and sunflower oil diets [analysis of variance (ANOVA), P < 0.05]. The size of IDL, VLDL, and LDL subfractions did not differ between the diets, whereas a significantly higher number (apolipoprotein B concentration) and lipid content of the larger and medium-sized LDL subfractions were observed after the olive oil diet compared with the rapeseed oil and sunflower oil diets (ANOVA, P < 0.05). Total HDL cholesterol concentration did not differ significantly, but HDL(2a) cholesterol was higher after olive oil and rapeseed oil compared with sunflower oil (ANOVA, P < 0.05).In conclusion, rapeseed oil and sunflower oil had more favorable effects on blood lipids and plasma apolipoproteins as well as on the number and lipid content of LDL subfractions compared with olive oil. Some of the differences may be attributed to differences in the squalene and phytosterol contents of the oils.

  6. Trichosanatine alleviates oxidized low-density lipoprotein induced endothelial cells injury via inhibiting the LOX-1/p38 MAPK pathway.

    PubMed

    Zhang, Lei; Jia, Yu-Hua; Zhao, Xiao-Shan; Zhou, Feng-Hua; Pan, Yun-Yun; Wan, Qiang; Cui, Xiao-Bing; Sun, Xue-Gang; Chen, Yu-Yao; Zhang, Yu; Cheng, Sai-Bo

    2016-01-01

    The LOX-1/p38 mitogen-activated protein kinase (MAPK) pathway has been proved to participate in the endothelial dysfunction in atherosclerosis. Trichosanatineis is an active compound isolated from the peel of Trichosanthes kirilowii. This study aims to determine whether trichosanatine prevents the oxidized low-density lipoprotein (ox-LDL)-induced insult through inhibition of the LOX-1/p38 MAPK pathway in HUVECs. HUVECs were treated with 150 mg/ml ox-LDL for 24 h to establish an ox-LDL-induced endothelial injury model. Cell viability, mitochondrial membrane potential (MMP), apoptosis, reactive oxygen species (ROS) level, LOX-1 and p38 MAPK expression level were measured. The results indicated that HUVECs were pretreated with either 100 mM trichosanatine or LOX-1 shRNA prior to exposure to ox-LDL for 24 h. Exposure of HUVECs to 150 mg/ml ox-LDL for 24 h significantly up-regulated the expression levels of LOX-1. The increased expression levels of LOX-1 were markedly attenuated by pretreatment with 100 mM trichosanatine. In addition, the ox-LDL-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with LOX-1 shRNA. Pretreatment of HUVECs with either trichosanatine or LOX-1 shRNA before exposure to ox-LDL significantly inhibited the ox-LDL-induced injuries, as evidenced by an increase in cell viability, a decrease in apoptotic cells, a ROS generation and a loss of MMP. In conclusion, we have demonstrated for the first time that the LOX-1/p38 MAPK pathway contributes to the ox-LDL-induced injury in HUVECs. Meanwhile, the trichosanatine protects the HUVECs against ox-LDL-induced injury at least in part by inhibiting the activated of LOX-1/p38 MAPK pathway.

  7. Trichosanatine alleviates oxidized low-density lipoprotein induced endothelial cells injury via inhibiting the LOX-1/p38 MAPK pathway

    PubMed Central

    Zhang, Lei; Jia, Yu-Hua; Zhao, Xiao-Shan; Zhou, Feng-Hua; Pan, Yun-Yun; Wan, Qiang; Cui, Xiao-Bing; Sun, Xue-Gang; Chen, Yu-Yao; Zhang, Yu; Cheng, Sai-Bo

    2016-01-01

    The LOX-1/p38 mitogen-activated protein kinase (MAPK) pathway has been proved to participate in the endothelial dysfunction in atherosclerosis. Trichosanatineis is an active compound isolated from the peel of Trichosanthes kirilowii. This study aims to determine whether trichosanatine prevents the oxidized low-density lipoprotein (ox-LDL)-induced insult through inhibition of the LOX-1/p38 MAPK pathway in HUVECs. HUVECs were treated with 150 mg/ml ox-LDL for 24 h to establish an ox-LDL-induced endothelial injury model. Cell viability, mitochondrial membrane potential (MMP), apoptosis, reactive oxygen species (ROS) level, LOX-1 and p38 MAPK expression level were measured. The results indicated that HUVECs were pretreated with either 100 mM trichosanatine or LOX-1 shRNA prior to exposure to ox-LDL for 24 h. Exposure of HUVECs to 150 mg/ml ox-LDL for 24 h significantly up-regulated the expression levels of LOX-1. The increased expression levels of LOX-1 were markedly attenuated by pretreatment with 100 mM trichosanatine. In addition, the ox-LDL-induced increase in phosphorylated (p) p38 MAPK expression was ameliorated by pretreatment with LOX-1 shRNA. Pretreatment of HUVECs with either trichosanatine or LOX-1 shRNA before exposure to ox-LDL significantly inhibited the ox-LDL-induced injuries, as evidenced by an increase in cell viability, a decrease in apoptotic cells, a ROS generation and a loss of MMP. In conclusion, we have demonstrated for the first time that the LOX-1/p38 MAPK pathway contributes to the ox-LDL-induced injury in HUVECs. Meanwhile, the trichosanatine protects the HUVECs against ox-LDL-induced injury at least in part by inhibiting the activated of LOX-1/p38 MAPK pathway. PMID:28078016

  8. Restoration of LDL receptor function in cells from patients with autosomal recessive hypercholesterolemia by retroviral expression of ARH1.

    PubMed

    Eden, Emily R; Patel, Dilipkumar D; Sun, Xi-Ming; Burden, Jemima J; Themis, Michael; Edwards, Matthew; Lee, Philip; Neuwirth, Clare; Naoumova, Rossitza P; Soutar, Anne K

    2002-12-01

    Familial hypercholesterolemia is an autosomal dominant disorder with a gene-dosage effect that is usually caused by mutations in the LDL receptor gene that disrupt normal clearance of LDL. In the homozygous form, it results in a distinctive clinical phenotype, characterized by inherited hypercholesterolemia, cholesterol deposition in tendons, and severe premature coronary disease. We described previously two families with autosomal recessive hypercholesterolemia that is not due to mutations in the LDL receptor gene but is characterized by defective LDL receptor-dependent internalization and degradation of LDL by transformed lymphocytes from the patients. We mapped the defective gene to chromosome 1p36 and now show that the disorder in these and a third English family is due to novel mutations in ARH1, a newly identified gene encoding an adaptor-like protein. Cultured skin fibroblasts from affected individuals exhibit normal LDL receptor activity, but their monocyte-derived macrophages are similar to transformed lymphocytes, being unable to internalize and degrade LDL. Retroviral expression of normal human ARH1 restores LDL receptor internalization in transformed lymphocytes from an affected individual, as demonstrated by uptake and degradation of (125)I-labeled LDL and confocal microscopy of cells labeled with anti-LDL-receptor Ab.

  9. Phospholipids in oxidized LDL not adducted to apoB are recognized by the CD36 scavenger receptor.

    PubMed

    Podrez, Eugene A; Hoppe, George; O'Neil, June; Hoff, Henry F

    2003-02-01

    Previous studies have shown that oxidation of low-density lipoprotein (oxLDL) results in its recognition by scavenger receptors on macrophages. Whereas blockage of lysyl residues on apoB-100 of oxLDL by lipid peroxidation products appears to be critical for recognition by the scavenger receptor class A (SR-A), modification of the lipid moiety has been suggested to be responsible for recognition by the scavenger class B receptor, CD36. We studied the recognition by scavenger receptors of oxidized LDL in which lysyl residues are blocked prior to oxidation through methylation [ox(m)LDL]. This permits us to minimize any contribution of modified apoB-100 to the recognition of oxLDL, but does not disrupt the native configuration of lipids in the particle. We found that ox(m)LDL was recognized by receptors on mouse peritoneal macrophages (MPM) almost as well as oxLDL. Ox(m)LDL was recognized by CD36-transfected cells but not by SR-A-transfected cells. Oxidized phospholipids (oxPC) transferred from oxLDL or directly from oxPC to LDL, conveyed recognition by CD36-transfected cells, confirming that CD36 recognized unbound oxidized phospholipids in ox(m)LDL. Collectively, these results suggest that oxPC not adducted to apoB within the intact oxLDL particle are recognized by the macrophage scavenger receptor CD36, that these lipids are not recognized by SR-A, and that they can transfer from oxidized to unoxidized LDL and induce CD36 recognition.

  10. Effect of shear stress on water and LDL transport through cultured endothelial cell monolayers.

    PubMed

    Kang, Hongyan; Cancel, Limary M; Tarbell, John M

    2014-04-01

    Previous animal experiments have shown that the transport of LDL into arterial walls is shear stress dependent. However, little work has probed shear effects on LDL transport in vitro where conditions are well defined and mechanisms are more easily explored. Therefore, we measured shear induced water and LDL fluxes across cultured bovine aortic endothelial (BAEC) monolayers in vitro and developed a three-pore model to describe the transport dynamics. Cell apoptosis was quantified by TdT-mediated dUTP nick end labeling (TUNEL) assay. We also examined the role of nitric oxide (NO) in shear induced water and LDL fluxes by incubating BAEC monolayers with an NO synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA). Our results show that direct exposure of endothelial monolayers to 12 dyn/cm2 shear stress for 3 h elicited a 2.37-fold increase in water flux (Jv), a 3.00-fold increase in LDL permeability (Pe), a 1.32-fold increase in LDL uptake, and a 1.68-fold increase in apoptotic rate. L-NMMA treatment of BAEC monolayers blocked shear induced Jv response, but had no significant effect on shear responses of Pe and cell apoptosis. A long time shear exposure (12 h) of endothelial monolayers reduced Pe and apoptotic rate close to the baseline. These results suggest that an acute change in shear stress from a static baseline state induces increases in water flux that are mediated by an NO dependent mechanism. On the other hand, the permeability of endothelial monolayers to LDL is enhanced by a short term-shear application and reduced nearly to the baseline level by a longer time shear exposure, positively correlated to the leaky junctions forming around apoptotic cells.

  11. Dust-acoustic shock waves in a charge varying electronegative magnetized dusty plasma with nonthermal ions: Application to Halley Comet plasma

    SciTech Connect

    Tribeche, Mouloud; Bacha, Mustapha

    2013-10-15

    Weak dust-acoustic waves (DAWs) are addressed in a nonthermal charge varying electronegative magnetized dusty plasmas with application to the Halley Comet. A weakly nonlinear analysis is carried out to derive a Korteweg-de Vries-Burger equation. The positive ion nonthermality, the obliqueness, and magnitude of the magnetic field are found to modify the dispersive and dissipative 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.

  12. The Effect of Hypertension on the Transport of LDL Across the Deformable Arterial Wall

    NASA Astrophysics Data System (ADS)

    Dabagh, Mahsa; Jalali, Payman

    2010-05-01

    The influences of increased endothelial cell turnover and deformation of the intima on the transport of low-density lipoprotein (LDL) under hypertension are investigated by applying a multilayered model of aortic wall. The thickness and properties of the endothelium, intima, internal elastic lamina (IEL), and media are affected by the transmural pressure. Navier-Stokes and Brinkman equations are applied for the transport of the transmural flow and the convective-diffusion equation is solved for LDL transport. LDL macromolecules enter the intima through leaky junctions, and then pass through the media layer where they permeate over the surface of smooth muscle cells (SMC). Uptake of LDL by cells is modeled through a uniform reaction evenly distributed in the macroscopically homogeneous media layer. The results show that transmural pressure significantly affects the LDL fluxes across the leaky junction, the intima, fenestral pores in the IEL, and the media layer. Many realistic predictions including the proper magnitudes for the permeability of endothelium and intimal layers, and the hydraulic conductivity of all layers as well as their trends with pressure are predicted by the present model.

  13. Spleen Tyrosine Kinase Regulates AP-1 Dependent Transcriptional Response to Minimally Oxidized LDL

    PubMed Central

    Choi, Soo-Ho; Wiesner, Philipp; Almazan, Felicidad; Kim, Jungsu; Miller, Yury I.

    2012-01-01

    Oxidative modification of low-density lipoprotein (LDL) turns it into an endogenous ligand recognized by pattern-recognition receptors. We have demonstrated that minimally oxidized LDL (mmLDL) binds to CD14 and mediates TLR4/MD-2-dependent responses in macrophages, many of which are MyD88-independent. We have also demonstrated that the mmLDL activation leads to recruitment of spleen tyrosine kinase (Syk) to TLR4 and TLR4 and Syk phosphorylation. In this study, we produced a macrophage-specific Syk knockout mouse and used primary Syk−/− macrophages in our studies. We demonstrated that Syk mediated phosphorylation of ERK1/2 and JNK, which in turn phosphorylated c-Fos and c-Jun, respectively, as assessed by an in vitro kinase assay. c-Jun phosphorylation was also mediated by IKKε. c-Jun and c-Fos bound to consensus DNA sites and thereby completed an AP-1 transcriptional complex and induced expression of CXCL2 and IL-6. These results suggest that Syk plays a key role in TLR4-mediated macrophage responses to host-generated ligands, like mmLDL, with subsequent activation of an AP-1 transcription program. PMID:22384232

  14. Oxidative modification and poor protective activity of HDL on LDL oxidation in thalassemia.

    PubMed

    Unchern, Supeenun; Laohareungpanya, Narumon; Sanvarinda, Yupin; Pattanapanyasat, Kovit; Tanratana, Pansakorn; Chantharaksri, Udom; Sibmooh, Nathawut

    2010-07-01

    Oxidative modification of low-density lipoprotein (LDL) has been reported in thalassemia, which is a consequence of oxidative stress. However, the levels of oxidized high-density lipoprotein (HDL) in thalassemia have not been evaluated and it is unclear whether HDL oxidation may be linked to LDL oxidation. In this study, the levels of total cholesterol, iron, protein, conjugated diene (CD), lipid hydroperoxide (LOOH), and thiobarbituric acid reactive substances (TBARs) were determined in HDL from healthy volunteers and patients with beta-thalassemia intermedia with hemoglobin E (beta-thal/Hb E). The protective activity of thalassemic HDL on LDL oxidation was also investigated. The iron content of HDL(2) and HDL(3) from beta-thal/HbE patients was higher while the cholesterol content was lower than those in healthy volunteers. Thalassemic HDL(2) and HDL(3) had increased levels of lipid peroxidation markers i.e., conjugated diene, LOOH, and TBARs. Thalassemic HDL had lower peroxidase activity than control HDL and was unable to protect LDL from oxidation induced by CuSO(4). Our findings highlight the oxidative modification and poor protective activity of thalassemic HDL on LDL oxidation which may contribute to cardiovascular complications in thalassemia.

  15. Effect of phytosterols/stanols on LDL concentration and other surrogate markers of cardiovascular risk.

    PubMed

    Bard, J-M; Paillard, F; Lecerf, J-M

    2015-02-01

    Plant sterols and stanols are well-known to reduce LDL-cholesterol (LDL-C) concentrations. It is generally accepted that supplementation with 2g/day of sterols/stanols leads to a 10% reduction in LDL. However, most of the clinical trials supporting this conclusion were of short-term duration, and the results of longer interventions are scanty. In four studies, interventions lasting>6 months were carried out and the LDL-C-lowering effects were maintained over this longer duration, although some results suggest that a reduced effect may be observed with sterols, while stanols maintain their effect. In any case, the data are too limited to be definitive. In a free-living population as well as in multiparametric interventional studies, however, the LDL-C-lowering effect has been confirmed, although to a lesser extent than in clinical studies. In the absence of data on cardiovascular morbidity and mortality, data for surrogate markers of cardiovascular risk could be considered adequate alternatives. Several studies have been conducted on this basis, but their results failed to demonstrate any favourable effects. The present report summarizes the different results obtained in long-term studies, and in those comparing the effects of sterols and stanols on lipids and other surrogate markers of cardiovascular risk.

  16. Isoforms of Hsp70-binding human LDL in adult Schistosoma mansoni worms.

    PubMed

    Pereira, Adriana S A; Cavalcanti, Marília G S; Zingali, Russolina B; Lima-Filho, José L; Chaves, Maria E C

    2015-03-01

    Schistosoma mansoni is one of the most common parasites infecting humans. They are well adapted to the host, and this parasite's longevity is a consequence of effective escape from the host immune system. In the blood circulation, lipoproteins not only help to conceal the worm from attack by host antibodies but also act as a source of lipids for S. mansoni. Previous SEM studies showed that the low-density lipoprotein (LDL) particles present on the surface of adult S. mansoni worms decreased in size when the incubation time increased. In this study, immunocytochemical and proteomic analyses were used to locate and identify S. mansoni binding proteins to human plasma LDL. Ultrathin sections of adult worms were cut transversely from the anterior, medial and posterior regions of the parasite. Immunocytochemical experiments revealed particles of gold in the tegument, muscle region and spine in male worms and around vitelline cells in females. Immunoblotting and 2D-electrophoresis using incubations with human serum, anti-LDL antibodies and anti-chicken IgG peroxidase conjugate were performed to identify LDL-binding proteins in S. mansoni. Analysis of the binding proteins using LC-MS identified two isoforms of the Hsp70 chaperone in S. mansoni. Hsp70 is involved in the interaction with apoB in the cytoplasm and its transport to the endoplasmic reticulum. However, further studies are needed to clarify the functional role of Hsp70 in S. mansoni, mainly related to the interaction with human LDL.

  17. Resolving Low-Density Lipoprotein (LDL) on the Human Aortic Surface Using Large Eddy Simulation

    NASA Astrophysics Data System (ADS)

    Lantz, Jonas; Karlsson, Matts

    2011-11-01

    The prediction and understanding of the genesis of vascular diseases is one of the grand challenges in biofluid engineering. The progression of atherosclerosis is correlated to the build- up of LDL on the arterial surface, which is affected by the blood flow. A multi-physics simulation of LDL mass transport in the blood and through the arterial wall of a subject specific human aorta was performed, employing a LES turbulence model to resolve the turbulent flow. Geometry and velocity measurements from magnetic resonance imaging (MRI) were incorporated to assure physiological relevance of the simulation. Due to the turbulent nature of the flow, consecutive cardiac cycles are not identical, neither in vivo nor in the simulations. A phase average based on a large number of cardiac cycles is therefore computed, which is the proper way to get reliable statistical results from a LES simulation. In total, 50 cardiac cycles were simulated, yielding over 2.5 Billion data points to be post-processed. An inverse relation between LDL and WSS was found; LDL accumulated on locations where WSS was low and vice-versa. Large temporal differences were present, with the concentration level decreasing during systolic acceleration and increasing during the deceleration phase. This method makes it possible to resolve the localization of LDL accumulation in the normal human aorta with its complex transitional flow.

  18. Glycaemic control influences the relationship between plasma PCSK9 and LDL cholesterol in type 1 diabetes.

    PubMed

    Laugier-Robiolle, Stéphanie; Vergès, Bruno; Le Bras, Maëlle; Gand, Elise; Bouillet, Benjamin; Saulnier, Pierre-Jean; Le May, Cédric; Pichelin, Matthieu; Maréchaud, Richard; Petit, Jean-Michel; Hadjadj, Samy; Cariou, Bertrand

    2017-03-01

    Pro-protein convertase subtilisin/kexin type 9 (PCSK9) is a critical regulator of LDL cholesterol metabolism. Little is known, however, about the regulation of PCSK9 in patients with type 1 diabetes (T1D). In the present study, we aimed to determine the relationship between circulating PCSK9 and metabolic variables in T1D. Plasma PCSK9 levels were measured in 195 people with T1D (mean age 38.8 years, mean diabetes duration 17.2 years, mean glycated haemoglobin [HbA1c] 8.3%), who were free of any lipid-lowering agent. Plasma PCSK9 was positively correlated with LDL cholesterol (P = .0007), triglycerides (P = .004), apolipoprotein B (P = .005), HbA1c (P = .003), systolic (P = .003) and diastolic (P = .001) blood pressure and body mass index (0.02). In multivariate analysis, PCSK9 concentration was independently associated with HbA1c (P = .02) and LDL cholesterol (P = .03). After classifying patients according to HbA1c tertile, the correlation between PCSK9 and LDL cholesterol was only observed in the highest tertile (P = .0006; Rho = 0.43), whereas no correlation was found in the lowest and intermediate tertiles. This study suggests that good glycaemic control abolishes the positive relationship between PCSK9 and LDL cholesterol in patients with T1D; however, the underlying molecular mechanisms remain to be established.

  19. Prediction of LDL concentration at the luminal surface of a vascular endothelium.

    PubMed

    Wada, Shigeo; Karino, Takeshi

    2002-01-01

    To find out whether concentration polarization of low-density lipoprotein (LDL) occurs at the surface of a vascular endothelium or not, transport of LDL in flowing blood to an water-permeable endothelium was studied theoretically by means of CFD. Calculations were carried out for an endothelium exposed to a Couette flow by assuming that the surface geometry of the endothelium could be expressed by a cosine function. Two typical cases were considered for the permeability of endothelium to water; one was uniform permeability everywhere in the endothelium, and the other was uneven permeability which was augmented at the intercellular junction. It was found that, in both cases, the surface concentration of LDL increased in going distally from the entrance, taking locally high and low values at the valleys and hills of the endothelium, respectively, and the variation was larger in the case of endothelium with uneven permeability. These results clearly showed that concentration polarization of LDL which might affect the uptake of LDL by the arterial wall certainly occurs at the surface of the endothelium even if the flow is disturbed microscopically by the uneven surface of the endothelium.

  20. [Study of LDL receptors and response to lovastatin therapy in familial homozygotic hypercholesterolemia].

    PubMed

    Ausina Gómez, A; Gilsanz Peral, A; Montero Brens, C; Dalmau Serra, J

    1991-11-01

    This study shows the results obtained with lovastatin as a combined therapy with probucol and cholestyramine on the lipid profile of two patients with homozygous familial hypercholesterolemia. Both have been diagnosed according to the clinical and biochemical criteria (tipe IIa hypercholesterolemia) as well as by the cholesterol or low density lipoprotein (LDL-C) receptor analysis. After the initial probucol and cholestyramine treatment we observed a drop of total cholesterol (T-C) of 41.7% and 46% as well as LDL-C of 51.6% and 49.3% in both patients. Respectively when lovastatin were associated an additional drop of T-C of 23.7%, LDL-C of 23.2%, high-density lipoprotein cholesterol (HDL-C) of 22.4% and the apoprotein B (Apo B) of 37% were obtained in one patient (receptor-defective) but no change in the lipid profile were obtained in the other patient (receptor-negative). No adverse effects were observed with this drug. This drug could be of help as a combined therapy in the treatment of homozygous familial hypercholesterolemia, even though the treatment of choice is the LDL-plasma feresis and/or liver transplantation. We expound the difficulties relate to LDL receptor study in homocygous receptor-negative patients.

  1. LDL-Cholesterol Increases the Transcytosis of Molecules through Endothelial Monolayers

    PubMed Central

    Magalhaes, Ana; Matias, Inês; Palmela, Inês; Brito, Maria Alexandra; Dias, Sérgio

    2016-01-01

    Cholesterol has been identified as a causative factor in numerous pathologies including atherosclerosis and cancer. One of the frequent effects of elevated cholesterol levels in humans is the compromise of endothelial function due to activation of pro-inflammatory signalling pathways. While the mechanisms involved in endothelial activation by cholesterol during an inflammatory response are well established, less is known about the mechanisms by which cholesterol may affect endothelial barrier function, which were the subject of the present study. Here we show that low density lipoprotein (LDL) increases the permeability of endothelial monolayers to high molecular weight dextrans in an LDL receptor and cholesterol-dependent manner. The increased permeability seen upon LDL treatment was not caused by disruption of cell-to-cell junctions as determined by a normal localization of VE-Cadherin and ZO-1 proteins, and no major alterations in transendothelial electrical resistance or permeability to fluorescein. We show instead that LDL increases the level of high molecular weight transcytosis and that this occurs in an LDL receptor, cholesterol and caveolae-dependent way. Our findings contribute to our understanding of the systemic pathological effects of elevated cholesterol and the transport of cargo through endothelial monolayers. PMID:27695052

  2. Pectin isolated from prickly pear (Opuntia SSP) modifies LDL metabolism in cholesterol-fed guinea pigs

    SciTech Connect

    Fernandez, M.L.; McNamara, D.J. )

    1990-02-26

    The effects of dietary pectin on plasma and hepatic cholesterol (CH) levels, plasma lipoprotein profiles, hepatic 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA) reductase activity, and low density lipoprotein (LDL) binding to hepatic membranes were investigated by feeding 1% pectin to guinea pigs on a high CH diet. Animals were fed either chow + 0.25% CH (HC diet) or the CH diet + 1% prickly pear pectin (HC-P diet) for 25 days. Plasma CH levels were decreased 26% by the HC-P with 33% decreases in LDL and KDL. LDL peak density shifted from 1.040 to 1.055 g/ml with pectin. Hepatic total, free and esterified CH levels were reduced 60, 40 and 85% respectively by the HC-P diet. In contrast, HMG-CoA reductase activity was unaffected. {sup 125}I-LDL binding to hepatic membranes was increased by intake of the HC-P diet compared to the HC diet. The affinity of the apo B/E receptor for LDL was not affected by dietary pectin while the receptor number was increased 1.5-fold in animals on the HC-P diet. These data suggest that the parameters of HC metabolism affected by dietary pectin are consistent with an increased demand on the hepatic CH pools which possibly results from increased fecal excretion of bile acids.

  3. Dihydrotanshinone I Attenuates Atherosclerosis in ApoE-Deficient Mice: Role of NOX4/NF-κB Mediated Lectin-Like Oxidized LDL Receptor-1 (LOX-1) of the Endothelium.

    PubMed

    Zhao, Wenwen; Li, Chunxia; Gao, Hongwei; Wu, Qin; Shi, Jingshan; Chen, Xiuping

    2016-01-01

    Dihydrotanshinone I (DHT) is a natural compound extracted from Salvia miltiorrhiza Bunge which has been widely used for treating cardiovascular diseases. However, its role in atherosclerosis remains unclear. In this study, the effect of DHT on atherosclerosis were investigated using apolipoprotein E-deficient (ApoE(-/-)) mice and endothelial cells. In lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), DHT (10 nM) decreased lectin-like ox-LDL receptor-1 (LOX-1) and NADPH oxidase 4 (NOX4) expression, reactive oxygen species (ROS) production, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. Silence NOX4 inhibited LPS-induced LOX-1 expression, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. In ApoE(-/-) mice fed with an atherogenic diet, DHT (10 and 25 mg kg(-1)) significantly attenuated atherosclerotic plaque formation, altered serum lipid profile, decreased oxidative stress and shrunk necrotic core areas. The enhanced expression of LOX-1, NOX4, and NF-κB in aorta was also dramatically inhibited by DHT. In conclusion, these results suggested that DHT showed anti-atherosclerotic activity through inhibition of LOX-1 mediated by NOX4/NF-κB signaling pathways both in vitro and in vivo. This finding suggested that DHT might be used as a potential vascular protective candidate for the treatment of atherosclerosis.

  4. Dihydrotanshinone I Attenuates Atherosclerosis in ApoE-Deficient Mice: Role of NOX4/NF-κB Mediated Lectin-Like Oxidized LDL Receptor-1 (LOX-1) of the Endothelium

    PubMed Central

    Zhao, Wenwen; Li, Chunxia; Gao, Hongwei; Wu, Qin; Shi, Jingshan; Chen, Xiuping

    2016-01-01

    Dihydrotanshinone I (DHT) is a natural compound extracted from Salvia miltiorrhiza Bunge which has been widely used for treating cardiovascular diseases. However, its role in atherosclerosis remains unclear. In this study, the effect of DHT on atherosclerosis were investigated using apolipoprotein E-deficient (ApoE-/-) mice and endothelial cells. In lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs), DHT (10 nM) decreased lectin-like ox-LDL receptor-1 (LOX-1) and NADPH oxidase 4 (NOX4) expression, reactive oxygen species (ROS) production, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. Silence NOX4 inhibited LPS-induced LOX-1 expression, NF-κB nuclear translocation, ox-LDL endocytosis and monocytes adhesion. In ApoE-/- mice fed with an atherogenic diet, DHT (10 and 25 mg kg-1) significantly attenuated atherosclerotic plaque formation, altered serum lipid profile, decreased oxidative stress and shrunk necrotic core areas. The enhanced expression of LOX-1, NOX4, and NF-κB in aorta was also dramatically inhibited by DHT. In conclusion, these results suggested that DHT showed anti-atherosclerotic activity through inhibition of LOX-1 mediated by NOX4/NF-κB signaling pathways both in vitro and in vivo. This finding suggested that DHT might be used as a potential vascular protective candidate for the treatment of atherosclerosis. PMID:27891092

  5. A shed form of LDL receptor–related protein–1 regulates peripheral nerve injury and neuropathic pain in rodents

    PubMed Central

    Gaultier, Alban; Arandjelovic, Sanja; Li, Xiaoqing; Janes, Julie; Dragojlovic, Nikola; Zhou, George P.; Dolkas, Jenny; Myers, Robert R.; Gonias, Steven L.; Campana, W. Marie

    2007-01-01

    Injury to the peripheral nervous system (PNS) initiates a response controlled by multiple extracellular mediators, many of which contribute to the development of neuropathic pain. Schwann cells in an injured nerve demonstrate increased expression of LDL receptor–related protein–1 (LRP1), an endocytic receptor for diverse ligands and a cell survival factor. Here we report that a fragment of LRP1, in which a soluble or shed form of LRP1 with an intact α-chain (sLRP-α), was shed by Schwann cells in vitro and in the PNS after injury. Injection of purified sLRP-α into mouse sciatic nerves prior to chronic constriction injury (CCI) inhibited p38 MAPK activation (P-p38) and decreased expression of TNF-α and IL-1β locally. sLRP-α also inhibited CCI-induced spontaneous neuropathic pain and decreased inflammatory cytokine expression in the spinal dorsal horn, where neuropathic pain processing occurs. In cultures of Schwann cells, astrocytes, and microglia, sLRP-α inhibited TNF-α–induced activation of p38 MAPK and ERK/MAPK. The activity of sLRP-α did not involve TNF-α binding, but rather glial cell preconditioning, so that the subsequent response to TNF-α was inhibited. Our results show that sLRP-α is biologically active and may attenuate neuropathic pain. In the PNS, the function of LRP1 may reflect the integrated activities of the membrane-anchored and shed forms of LRP1. PMID:18060043

  6. [LDL cholesterol control in patients with very high cardiovascular risk. A simplified algorithm for achieving LDL cholesterol goals "in two steps"].

    PubMed

    Guijarro-Herraiz, Carlos; Masana-Marin, Luis; Galve, Enrique; Cordero-Fort, Alberto

    2014-01-01

    Reducing low density lipoprotein-cholesterol (LDL-c) is the main lipid goal of treatment for patients with very high cardiovascular risk. In these patients the therapeutic goal is to achieve a LDL-c lower than 70 mg/dL, as recommended by the guidelines for cardiovascular prevention commonly used in Spain and Europe. However, the degree of achieving these objectives in this group of patients is very low. This article describes the prevalence of the problem and the causes that motivate it. Recommendations and tools that can facilitate the design of an optimal treatment strategy for achieving the goals are also given. In addition, a new tool with a simple algorithm that can allow these very high risk patients to achieve the goals "in two-steps", i.e., with only two doctor check-ups, is presented.

  7. Imaging and force measurement of LDL and HDL by AFM in air and liquid

    PubMed Central

    Gan, Chaoye; Ao, Meiying; Liu, Zhanghua; Chen, Yong

    2015-01-01

    The size and biomechanical properties of lipoproteins are tightly correlated with their structures/functions. While atomic force microscopy (AFM) has been used to image lipoproteins the force measurement of these nano-sized particles is missing. We detected that the sizes of LDL and HDL in liquid are close to the commonly known values. The Young’s modulus of LDL or HDL is ∼0.4 GPa which is similar to that of some viral capsids or nanovesicles but greatly larger than that of various liposomes. The adhesive force of LDL or HDL is small (∼200 pN). The comparison of AFM detection in air and liquid was also performed which is currently lacking. Our data may provide useful information for better understanding and AFM detection of lipoproteins. PMID:25893163

  8. Imaging and force measurement of LDL and HDL by AFM in air and liquid.

    PubMed

    Gan, Chaoye; Ao, Meiying; Liu, Zhanghua; Chen, Yong

    2015-01-01

    The size and biomechanical properties of lipoproteins are tightly correlated with their structures/functions. While atomic force microscopy (AFM) has been used to image lipoproteins the force measurement of these nano-sized particles is missing. We detected that the sizes of LDL and HDL in liquid are close to the commonly known values. The Young's modulus of LDL or HDL is ∼0.4 GPa which is similar to that of some viral capsids or nanovesicles but greatly larger than that of various liposomes. The adhesive force of LDL or HDL is small (∼200 pN). The comparison of AFM detection in air and liquid was also performed which is currently lacking. Our data may provide useful information for better understanding and AFM detection of lipoproteins.

  9. Inhibitory effect of natto, a kind of fermented soybeans, on LDL oxidation in vitro.

    PubMed

    Iwai, Kunihisa; Nakaya, Natsuko; Kawasaki, Yoshihiro; Matsue, Hajime

    2002-06-05

    The oxygen radical scavenging activity of natto (fermented soybeans) and its inhibitory effect on the oxidation of rat plasma low-density lipoprotein (LDL) in vitro were investigated to evaluate the usefulness of the antioxidant properties of natto, which has been shown to have antioxidant activity. Natto was separated into three water-soluble fractions: high-molecular-weight viscous substance (HMWVS; Mw > 100 000), low-molecular-weight viscous substance (LMWVS; Mw < 100 000), and soybean water extract (SWE). LMWVS had the strongest radical scavenging activity for hydroxyl and superoxide anion radicals, as assessed by electron spin resonance. The increase of conjugated dienes in LDL oxidized by copper and an azo pigment was depressed by the addition of LMWVS and SWE. These results demonstrate that natto fractions have inhibitory effects on LDL oxidation as a result of their radical scavenging activity.

  10. Impact of myeloperoxidase-LDL interactions on enzyme activity and subsequent posttranslational oxidative modifications of apoB-100

    PubMed Central

    Delporte, Cédric; Boudjeltia, Karim Zouaoui; Noyon, Caroline; Furtmüller, Paul G.; Nuyens, Vincent; Slomianny, Marie-Christine; Madhoun, Philippe; Desmet, Jean-Marc; Raynal, Pierre; Dufour, Damien; Koyani, Chintan N.; Reyé, Florence; Rousseau, Alexandre; Vanhaeverbeek, Michel; Ducobu, Jean; Michalski, Jean-Claude; Nève, Jean; Vanhamme, Luc; Obinger, Christian; Malle, Ernst; Van Antwerpen, Pierre

    2014-01-01

    Oxidation of LDL by the myeloperoxidase (MPO)-H2O2-chloride system is a key event in the development of atherosclerosis. The present study aimed at investigating the interaction of MPO with native and modified LDL and at revealing posttranslational modifications on apoB-100 (the unique apolipoprotein of LDL) in vitro and in vivo. Using amperometry, we demonstrate that MPO activity increases up to 90% when it is adsorbed at the surface of LDL. This phenomenon is apparently reflected by local structural changes in MPO observed by circular dichroism. Using MS, we further analyzed in vitro modifications of apoB-100 by hypochlorous acid (HOCl) generated by the MPO-H2O2-chloride system or added as a reagent. A total of 97 peptides containing modified residues could be identified. Furthermore, differences were observed between LDL oxidized by reagent HOCl or HOCl generated by the MPO-H2O2-chloride system. Finally, LDL was isolated from patients with high cardiovascular risk to confirm that our in vitro findings are also relevant in vivo. We show that several HOCl-mediated modifications of apoB-100 identified in vitro were also present on LDL isolated from patients who have increased levels of plasma MPO and MPO-modified LDL. In conclusion, these data emphasize the specificity of MPO to oxidize LDL. PMID:24534704

  11. Familial ligand-defective apolipoprotein B. Identification of a new mutation that decreases LDL receptor binding affinity.

    PubMed Central

    Pullinger, C R; Hennessy, L K; Chatterton, J E; Liu, W; Love, J A; Mendel, C M; Frost, P H; Malloy, M J; Schumaker, V N; Kane, J P

    1995-01-01

    Detection of new ligand-defective mutations of apolipoprotein B (apoB) will enable identification of sequences involved in binding to the LDL receptor. Genomic DNA from patients attending a lipid clinic was screened by single-strand conformation polymorphism analysis for novel mutations in the putative LDL receptor-binding domain of apoB-100. A 46-yr-old woman of Celtic and Native American ancestry with primary hypercholesterolemia (total cholesterol [TC] 343 mg/dl; LDL cholesterol [LDL-C] 241 mg/dl) and pronounced peripheral vascular disease was found to be heterozygous for a novel Arg3531-->Cys mutation, caused by a C-->T transition at nucleotide 10800. One unrelated 59-yr-old man of Italian ancestry was found with the same mutation after screening 1,560 individuals. He had coronary heart disease, a TC of 310 mg/dl, and an LDL-C of 212 mg/dl. A total of eight individuals were found with the defect in the families of the two patients. They had an age- and sex-adjusted TC of 240 +/- 14 mg/dl and LDL-C of 169 +/- 10 mg/dl. This compares with eight unaffected family members with age- and sex-adjusted TC of 185 +/- 12 mg/dl and LDL-C of 124 +/- 12 mg/dl. In a dual-label fibroblast binding assay, LDL from the eight subjects with the mutation had an affinity for the LDL receptor that was 63% that of control LDL. LDL from eight unaffected family members had an affinity of 91%. By way of comparison, LDL from six patients heterozygous for the Arg3500-->Gln mutation had an affinity of 36%. The percentage mass ratio of the defective Cys3531 LDL to normal LDL was 59:41, as determined using the mAb MB19 and dynamic laser light scattering. Thus, the defective LDL had accumulated in the plasma of these patients. Using this mass ratio, it was calculated that the defective Cys3531 LDL particles bound with 27% of normal affinity. Deduced haplotypes using 10 apoB gene markers showed the Arg3531-->Cys alleles to be different in the two kindreds and indicates that the mutations arose

  12. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.

    PubMed

    Benjannet, Suzanne; Rhainds, David; Essalmani, Rachid; Mayne, Janice; Wickham, Louise; Jin, Weijun; Asselin, Marie-Claude; Hamelin, Josée; Varret, Mathilde; Allard, Delphine; Trillard, Mélanie; Abifadel, Marianne; Tebon, Angie; Attie, Alan D; Rader, Daniel J; Boileau, Catherine; Brissette, Louise; Chrétien, Michel; Prat, Annik; Seidah, Nabil G

    2004-11-19

    The discovery of autosomal dominant hypercholesterolemic patients with mutations in the PCSK9 gene, encoding the proprotein convertase NARC-1, resulting in the missense mutations suggested a role in low density lipoprotein (LDL) metabolism. We show that the endoplasmic reticulum-localized proNARC-1 to NARC-1 zymogen conversion is Ca2+-independent and that within the zymogen autocatalytic processing site SSVFAQ [downward arrow]SIP Val at P4 and Pro at P3' are critical. The S127R and D374Y mutations result in approximately 50-60% and > or =98% decrease in zymogen processing, respectively. In contrast, the double [D374Y + N157K], F216L, and R218S natural mutants resulted in normal zymogen processing. The cell surface LDL receptor (LDLR) levels are reduced by 35% in lymphoblasts of S127R patients. The LDLR levels are also reduced in stable HepG2 cells overexpressing NARC-1 or its natural mutant S127R, and this reduction is abrogated in the presence of 5 mm ammonium chloride, suggesting that overexpression of NARC-1 increases the turnover rate of the LDLR. Adenoviral expression of wild type human NARC-1 in mice resulted in a maximal approximately 9-fold increase in circulating LDL cholesterol, while in LDLR-/- mice a delayed approximately 2-fold increase in LDL cholesterol was observed. In conclusion, NARC-1 seems to affect both the level of LDLR and that of circulating apoB-containing lipoproteins in an LDLR-dependent and -independent fashion.

  13. A feedback regulatory pathway between LDL and alpha-1 proteinase inhibitor in chronic inflammation and infection.

    PubMed

    Bristow, Cynthia L; Modarresi, Rozbeh; Babayeva, Mariya A; LaBrunda, Michelle; Mukhtarzad, Roya; Trucy, Maylis; Franklin, Aaron; Reeves, Rudy E R; Long, Allegra; Mullen, Michael P; Cortes, Jose; Winston, Ronald

    2013-11-01

    Dietary lipids are transported via lymph to the liver and transformed to lipoproteins which bind to members of the low density lipoprotein receptor family (LDL-RFMs). Certain LDL-RFMs, e.g., very low density lipoprotein receptor (VLDLR), are also bound by inactivated proteinase inhibitors, the most abundant being α1proteinase inhibitor (α1PI, α1antitrypsin). Inflammation/infection, including HIV-1 infection, is accompanied by low levels of CD4+ T cells and active α1PI and high levels of inactivated α1PI. By inducing LDL-RFMs-mediated cellular locomotion, active α1PI regulates the number of CD4+ T cells. We sought to investigate whether CD4+ T cells and α1PI directly impact lipoprotein levels. At the cellular level, we show that active α1PI is required for VLDLR-mediated uptake of receptor-associated cargo, specifically CD4-bound HIV-1. We show that active α1PI levels linearly correlate with LDL levels in HIV-1 infected individuals (P<0.001) and that therapeutic, weekly infusions of active α1PI elevate the number of CD4+ T cells and HDL levels while lowering LDL levels in patients on antiretroviral therapy with controlled HIV-1. Based on the unusual combination of lipodystrophy and low levels of α1PI and CD4+ T cells in HIV-1 disease, we reveal that LDL and α1PI participate in a feedback regulatory pathway. We demonstrate integral roles for sequentially acting active and inactive α1PI in the uptake and recycling of receptors and cargo aggregated with VLDLR including CD4 and chemokine receptors. Evidence supports a role for α1PI as a primary sentinel to deploy the immune system as a consequence of its role in lipoprotein transport.

  14. Postprandial decrease in LDL-cholesterol in men with metabolic syndrome

    PubMed Central

    Turczyn, Barbara; Wojakowska, Anna; Kreczyńska, Bogusława; Skoczyńska, Marta; Wojtas, Kamila

    2015-01-01

    Background In some epidemiological studies, blood lipids are determined at non-fasting state, which may impact cardiovascular risk estimation. The aim of this study was to evaluate postprandial LDL-C changes in men with newly diagnosed metabolic syndrome (MetSy). Methods 36 male patients were examined: 12 men with and 24 men without MetSy. The fat tolerance test was performed before and after a three-month hypolipidemic treatment. Serum lipids were measured using routine methods, lipid peroxides (LPO) colorimetrically, apolipoproteins A-I, B, and hsCRP immunoturbidimetrically. Results The postprandial increase in triglycerides was associated with a decrease in LDL-C and a small decrease in apo B. In men with MetSy, the mean change in LDL-C (−19.5 ± 2.3 mg/dl) was greater than in healthy men (−5.7 ± 3.8 mg/dl). All lipid changes (ΔTG, ΔLDL-C and ΔLPO) were linearly dependent on the postprandial non-LDL-cholesterol. After three months of hypolipidemic treatment, in all men with MetSy, the apoB/apoA-I ratio remained the same as before the therapy. Conclusion In men diagnosed with MetSy, postprandial decreases in LDL-cholesterol may cause underestimation of cardiovascular risk. After three months of hypolipidemic treatment, there was only a partial reduction in this risk, as the apoB/apoA-I ratio remained the same.

  15. [Update of planning tables of cholesterol-lowering therapy orientated to achieve LDL therapeutic targets].

    PubMed

    Masana, Luis; Plana, Núria

    2015-01-01

    This is the third update of a planning-table for use in cholesterol-lowering therapy, so as to obtain LDLc objectives. This is an easy to use laptop tool to help choose the best statin or combination therapy (statin plus ezetimibe) depending on the current LDL concentration of the patient, and the LDLc objective to achieve. It is based on a colour code that indicates the drugs that are efficient enough to help patients to achieve their LDL goal. Along with the table, recommendations are given for the best strategy in order to implement the optimal therapy in a maximum of two clinical encounters.

  16. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.

    PubMed

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A; Barnes, Michael R; Li, Xiaohui; Warren, Helen R; Chasman, Daniel I; Zhou, Kaixin; Arsenault, Benoit J; Donnelly, Louise A; Wiggins, Kerri L; Avery, Christy L; Griffin, Paula; Feng, QiPing; Taylor, Kent D; Li, Guo; Evans, Daniel S; Smith, Albert V; de Keyser, Catherine E; Johnson, Andrew D; de Craen, Anton J M; Stott, David J; Buckley, Brendan M; Ford, Ian; Westendorp, Rudi G J; Slagboom, P Eline; Sattar, Naveed; Munroe, Patricia B; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C; O'Brien, Eoin; Shaw-Hawkins, Sue; Chen, Y-D Ida; Nickerson, Deborah A; Smith, Joshua D; Dubé, Marie Pierre; Boekholdt, S Matthijs; Hovingh, G Kees; Kastelein, John J P; McKeigue, Paul M; Betteridge, John; Neil, Andrew; Durrington, Paul N; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C; Rice, Kenneth; Smith, Nicholas L; Lumley, Thomas; Whitsel, Eric A; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S; O'Donnell, Christopher J; Vasan, Ramachandran S; Wei, Wei-Qi; Wilke, Russell A; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M; Stafford, Jeanette M; Ding, Jingzhong; Herrington, David M; Kritchevsky, Stephen B; Eiriksdottir, Gudny; Launer, Leonore J; Harris, Tamara B; Chu, Audrey Y; Giulianini, Franco; MacFadyen, Jean G; Barratt, Bryan J; Nyberg, Fredrik; Stricker, Bruno H; Uitterlinden, André G; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H; Ridker, Paul M; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C; Ballantyne, Christie M; Rotter, Jerome I; Adrienne Cupples, L; Psaty, Bruce M; Palmer, Colin N A; Tardif, Jean-Claude; Colhoun, Helen M; Hitman, Graham; Krauss, Ronald M; Wouter Jukema, J; Caulfield, Mark J

    2014-10-28

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

  17. Prosopis farcta beans increase HDL cholesterol and decrease LDL cholesterol in ostriches (Struthio camelus).

    PubMed

    Omidi, Arash; Ansari nik, Hossein; Ghazaghi, Mahmood

    2013-02-01

    Ten blue-neck male ostriches (Struthio camelus) were fed Prosopis farcta beans throughout a 30-day experiment. Blood samples were collected from ostriches on days 0 and 30 to measure levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, total serum protein, albumin, globulin, cholesterol, calcium, inorganic phosphorus, the activity of aspartate aminotransferase, alanine aminotransferase, and γ-glutamyl transferase (γ-GT). From days 0 to 30, HDL cholesterol, total protein, and globulins levels increased significantly whereas LDL cholesterol, inorganic phosphorus, and γ-GT activity decreased significantly.

  18. Weight loss associated with reduced intake of carbohydrate reduces the atherogenicity of LDL in premenopausal women.

    PubMed

    Lofgren, Ingrid; Zern, Tosca; Herron, Kristin; West, Kristy; Sharman, Matthew J; Volek, Jeff S; Shachter, Neil S; Koo, Sung I; Fernandez, Maria Luz

    2005-09-01

    The effect of a 3-tier intervention including dietary modifications (ie, moderate energy restriction, decreased carbohydrate, increased protein), increased physical activity, and the use of carnitine as a dietary supplement was evaluated on plasma lipids and the atherogenicity of low-density lipoprotein (LDL) particles in a population of overweight and obese premenopausal (aged 20-45 years) women. Carnitine or a placebo (cellulose) was randomly assigned to the participants using a double-blind design. Carnitine supplementation was postulated to enhance fat oxidation resulting in lower concentrations of plasma triglycerides. Seventy women completed the 10-week protocol, which followed a reduction in their energy intake by 15% and a macronutrient energy distribution of 30% protein, 30% fat, and 40% carbohydrate. In addition, subjects increased the number of steps taken per day by 4500. As no differences were observed between the carnitine and placebo groups in all the measured parameters, all subjects were pooled together for statistical analysis. Participants decreased (P<.01) their caloric intake (between 4132.8 and 7770 kJ) and followed prescribed dietary modifications as assessed by dietary records. The average number of steps increased from 8950+/-3432 to 12764+/-4642 (P<.001). Body weight, plasma total cholesterol, LDL cholesterol, and triglyceride were decreased by 4.5%, 8.0%, 12.3%, and 19.2% (P<.0001), respectively, after the intervention. Likewise, apolipoproteins B and E decreased by 4.5% and 15% (P<.05) after 10 weeks. The LDL mean particle size was increased from 26.74 to 26.86 nm (P<.01), and the percent of the smaller LDL subfraction (P<.05) was decreased by 26.5% (P<.05) after 10 weeks. In addition, LDL lag time increased by 9.3% (P<.01), and LDL conjugated diene formation decreased by 23% (P<.01), indicating that the susceptibility of LDL to oxidation was decreased after the intervention. This study suggests that moderate weight loss (<5% of body

  19. Dose-dependent LDL-cholesterol lowering effect by plant stanol ester consumption: clinical evidence

    PubMed Central

    2012-01-01

    Elevated serum lipids are linked to cardiovascular diseases calling for effective therapeutic means to reduce particularly LDL-cholesterol (LDL-C) levels. Plant stanols reduce levels of LDL-C by partly blocking cholesterol absorption. Accordingly the consumption of foods with added plant stanols, typically esterified with vegetable oil fatty acids in commercial food products, are recommended for lowering serum cholesterol levels. A daily intake of 1.5 to 2.4 g of plant stanols has been scientifically evaluated to lower LDL-C by 7 to 10% in different populations, ages and with different diseases. Based on earlier studies, a general understanding is that no further reduction may be achieved in intakes in excess of approximately 2.5 g/day. Recent studies however suggest that plant stanols show a continuous dose–response effect in serum LDL-C lowering. This review discusses the evidence for a dose-effect relationship between plant stanol ester consumption and reduction of LDL-C concentrations with daily intakes of plant stanols of 4 g/day or more. We identified five such studies and the overall data demonstrate a linear dose-effect relationship with the most pertinent LDL-Cholesterol lowering outcome, 18%, achieved by a daily intake of 9 to 10 g of plant stanols. Along with reduction in LDL-C, the studies demonstrated a decrease in cholesterol absorption markers, the serum plant sterol to cholesterol ratios, by increasing the dose of plant stanol intake. None of the studies with daily intakes up to 10 g of plant stanols reported adverse clinical or biochemical effects from plant stanols. In a like manner, the magnitude of decrease in serum antioxidant vitamins was not related to the dose of plant stanols consumed and the differences between plant stanol ester consumers and controls were minor and insignificant or nonexisting. Consumption of plant stanols in high doses is feasible as a range of food products are commercially available for consumption including spreads

  20. Genetically determined hypercholesterolemia in a rhesus monkey family due to a deficiency of the LDL receptor.

    PubMed

    Scanu, A M; Khalil, A; Neven, L; Tidore, M; Dawson, G; Pfaffinger, D; Jackson, E; Carey, K D; McGill, H C; Fless, G M

    1988-12-01

    A family of rhesus monkeys comprising a sire, a dam, and four male offspring were fed a cholesterol-free Purina Chow diet for several months. The sire, 431-J, and two of the offspring, B-8204 and B-8806, had persistent plasma cholesterol levels in the range of 100-130 mg/dl, whereas the dam, 766-I, and the two other offspring, B-1000 and B-7643, exhibited a marked hypercholesterolemia in the 250-300 mg/dl range associated with an elevation of plasma LDL and apoB. When fed for 12 weeks a diet containing 12.5% lard and 0.25% cholesterol, sire, dam, B-1000 and B-7643 exhibited a marked hypercholesterolemia (500-800 mg/dl range), whereas B-8204 and B-8806 developed only a modest hypercholesterolemia (200-250 mg/dl). All animals were Lp[a]+. Skin fibroblasts from each animal and from control cells were grown in 10% fetal calf serum, transferred to 10% lipoprotein-deficient serum for 48 hr, and then incubated at 4 degrees C or 37 degrees C with 125I-labeled Lp[a]-free LDL. The fibroblasts from dam and offspring B-1000 and B-7643 bound and internalized 125I-labeled LDL less efficiently than control cells. Mathematical analyses of the 4 degrees C binding data indicated that there were no significant differences in LDL binding affinity between test and control cells suggesting that cells from the animals with a spontaneous hypercholesterolemia had a decreased number of LDL receptors. This conclusion was supported by the results of ligand and immunoblot analyses carried out on cell lysates separated by gradient gel electrophoresis. We conclude that a genetically determined LDL receptor deficiency was responsible, in part, for the spontaneous hypercholesterolemia observed in three out of the six family members and that this deficiency accounted for the hyperresponsiveness to a dietary fat and cholesterol challenge by the dam and the two offspring, B-1000 and B-7643. The hyperresponsiveness noted in the sire that had no evidence for LDL-receptor deficiency illustrates that

  1. Anticoagulant activity of tissue factor pathway inhibitor in human plasma is preferentially associated with dense subspecies of LDL and HDL and with Lp(a).

    PubMed

    Lesnik, P; Vonica, A; Guérin, M; Moreau, M; Chapman, M J

    1993-07-01

    Human plasma contains a multivalent, Kunitz-type proteinase inhibitor termed tissue factor pathway inhibitor (TFPI), which specifically inhibits the action of the factor VII(a)-tissue factor complex in coagulation. In the present study, we examined the distribution and anticoagulant activity of TFPI among plasma lipoprotein subspecies separated by isopycnic density gradient ultracentrifugation; this procedure permitted the simultaneous fractionation of the major lipoprotein classes (very-low-density lipoprotein [VLDL], intermediate-density lipoprotein [IDL], low-density lipoprotein [LDL], high-density lipoprotein [HDL] 2 and 3, and very-high-density lipoprotein [VHDL]). Studies of eight normolipidemic subjects revealed two major lipoprotein carriers of TFPI activity: dense LDL subspecies (d = 1.039 to 1.063 g/mL) and both dense HDL particles and VHDL (d = 1.133 to 1.190 g/mL), representing 33.8% and 35.9%, respectively, of the total lipoprotein-associated TFPI activity in plasma. TFPI activity was also associated with lipoprotein(a) (Lp[a]), whose density distribution (d = 1.044 to 1.100 g/mL) overlapped that of LDL and HDL2; such association was related to Lp(a)'s particle size and phenotype. VLDL, IDL, and LDL1 through LDL3 (d = 1.019 to 1.039 g/mL), HDL2 (d = 1.063 to 1.100 g/mL), and light subfractions of HDL3 (d = 1.100 to 1.167 g/mL) conveyed only 1.8%, 10%, and 18.5%, respectively, of lipoprotein-associated TFPI activity. Such anticoagulant activity was dependent on the presence of TFPI protein. The dense subspecies of HDL3 (d = 1.133 to 1.167 g/mL) with which TFPI was preferentially associated were small, displayed a cholesteryl ester to protein ratio of approximately 0.2, and were deficient in phospholipid (13.6% to 18.3%). HDL subspecies of d = 1.110 to 1.167 g/mL mainly contained the higher relative molecular mass form of TFPI of 41 kD (a form that is known to be covalently associated with apolipoprotein [apo] A-II) and minor bands of the 35- and 52-k

  2. Changes in LDL and HDL subclasses in normal pregnancy and associations with birth weight, birth length and head circumference.

    PubMed

    Zeljkovic, Aleksandra; Vekic, Jelena; Spasic, Slavica; Jelic-Ivanovic, Zorana; Spasojevic-Kalimanovska, Vesna; Gojkovic, Tamara; Ardalic, Daniela; Mandic-Markovic, Vesna; Cerovic, Nikola; Mikovic, Zeljko

    2013-04-01

    Pregnancy is associated with alterations in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, but the exact pattern of these variations remains controversial. This study investigates longitudinal changes of plasma LDL and HDL particles distributions during the course of normal pregnancy, as well as associations of maternal LDL and HDL subclasses distributions before delivery with parameters of newborn size. Blood samples were collected from 41 healthy pregnant women throughout entire pregnancy, before delivery and 7 weeks postpartum. LDL and HDL subclasses were determined by gradient gel electrophoresis, while other biochemical parameters were measured by standard laboratory methods. During gestation LDL size significantly decreased (P < 0.001), due to reduction in relative proportion of LDL I (P < 0.01) and increase of LDL II (P < 0.001) and IIIA (P < 0.05) subclasses. In the same time, HDL size and proportions of HDL 2a particles significantly decreased (P < 0.001), with concomitant increase of HDL 3b and 3c subclasses (P < 0.05). Observed alterations were associated with changes in serum triglyceride levels. Rearrangement in LDL subclasses distribution during gestation was transient, while postpartum HDL subclasses distribution remained shifted toward smaller particles. Higher proportion of LDL IVB in maternal plasma before delivery was an independent predictor of smaller birth weights and lengths, while higher proportions of LDL IVB and HDL 2a subclasses were independent determinants of newborns' smaller head circumferences. Routine gestational and prenatal care in otherwise normal pregnancy could be complemented with evaluation of LDL and HDL particles distribution in order to ensure an adequate size of the newborn.

  3. Notoginsenoside R1 inhibits oxidized low-density lipoprotein induced inflammatory cytokines production in human endothelial EA.hy926 cells.

    PubMed

    Su, Ping; Du, Shijing; Li, Hang; Li, Zhi; Xin, Wenfeng; Zhang, Wensheng

    2016-01-05

    Notoginsenoside R1 (NG-R1), a unique and main active ingredient of Panax notoginseng, has been described to exhibit anti-inflammatory activity. However, its protective effects against oxidized low-density lipoprotein (oxLDL)-induced inflammatory injury in vascular endothelial cells have not been clarified. In the present study, we have evaluated the anti-inflammatory effects of NG-R1 on oxLDL-induced endothelial cells and its possible molecular mechanism of action. Our results showed that NG-R1 treatment significantly attenuated oxLDL-induced expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β. These effects were accompanied with suppression of oxLDL-induced activation of NF-κB and Mitogen-activated protein kinases (MAPK). Moreover, NG-R1 also increased in Peroxisome proliferator-activated receptor γ (PPARγ) protein expression and transcription levels, and attenuated oxLDL-induced suppression of PPARγ expression. The inhibition of NG-R1 on oxLDL-induced TNF-α and IL-1β productions can be reversed by PPARγ antagonist GW9662. In conclusion, these data suggested that NG-R1 could suppress oxLDL-induced inflammatory cytokines production via activating PPARγ, which subsequently inhibiting oxLDL-induced NF-κB and MAPK activation.

  4. Inhibition of human low-density lipoprotein oxidation in vitro by Maharishi Ayur-Veda herbal mixtures.

    PubMed

    Sharma, H M; Hanna, A N; Kauffman, E M; Newman, H A

    1992-12-01

    In this study, we examined the effect of the Maharishi Ayur-Veda herbal mixtures (MAHMs) Maharishi Amrit Kalash-4 and -5 (M-4 and M-5), MA-631, and Maharishi Coffee Substitute (MCS) on low-density lipoprotein (LDL) oxidation and compared the potency of these mixtures to ascorbic acid, alpha-tocopherol, and probucol. LDL was incubated in 95% air and 5% CO2, with or without 3 microM Cu(+2), in the presence or absence of MAHMs, for 6 or 24 h. In a separate experiment, LDL was incubated as above except MAHMs were added at 0, 1.5, and 3.5 h after incubation started to assess their effect on initiation and propagation of LDL oxidation. Our results demonstrate that MAHMs caused concentration-dependent inhibition of LDL oxidation as assessed by thiobarbituric acid-reactive substances and electrophoretic mobility. The MAHM showed more antioxidant potency in preventing LDL oxidation than ascorbic acid, alpha-tocopherol, or probucol. Also, MAHMs inhibited both initiation and propagation of cupric ion-catalyzed LDL oxidation. These results suggest the importance of further research on these herbal mixtures in the investigation of atherosclerosis and free radical-induced injury.

  5. Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans

    PubMed Central

    Pavlyha, Marianna; Ngai, Colleen; Thomas, Tiffany; Holleran, Stephen; Ramakrishnan, Rajasekhar; Karmally, Wahida; Nandakumar, Renu; Fontanez, Nelson; Obunike, Joseph; Marcovina, Santica M.; Lichtenstein, Alice H.; Matthan, Nirupa R.; Matta, James; Maroccia, Magali; Becue, Frederic; Poitiers, Franck; Swanson, Brian; Cowan, Lisa; Sasiela, William J.; Surks, Howard K.

    2017-01-01

    Background: Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date. Methods: Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured. Results: Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations. Conclusions: Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL

  6. Radiolabeled cholesteryl ethers trace LDL cholesteryl esters but not HDL cholesteryl esters in the rat.

    PubMed

    Terpstra, A H

    1995-01-06

    The intravascular metabolism of cholesteryl [1-14C]oleoyl ester and [1,2-3H(N)]cholesteryl palmityl ether was compared in the rat, an animal species without plasma cholesteryl ester transfer activity (CETA). The tracers had identical plasma disappearance rates when they were incorporated into human or rat low density lipoproteins (LDL). Fractional catabolic rates (FCR) were 0.081 +/- 0.014 h-1 and 0.080 +/- 0.013 h-1 for human LDL ester and ether and 0.098 +/- 0.007 h-1 and 0.101 +/- 0.007 h-1 for rat LDL ester and ether, respectively. In contrast, the ether had plasma disappearance rates that were 24%-25% lower than the ester when they were incorporated into human or rat high density lipoproteins (HDL). FCR were 0.230 +/- 0.020 and 0.173 +/- 0.030 h-1 for human HDL ester and ether and 0.131 +/- 0.020 h-1 and 0.100 +/- 0.017 h-1 for rat HDL ester and ether respectively. Biological screening of the rat HDL preparations did not affect these differences. The results of these studies indicate that in the absence of plasma CETA, cholesteryl ethers can be used to trace LDL cholesteryl esters but not to trace HDL cholesteryl esters.

  7. Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms

    PubMed Central

    Zhao, Juan; Zhang, Qi; Tian, Liming; Huang, Wenhui; Quan, Jinxing; Wang, Jinyang; Xu, Yanjia; Wang, Yunfang; Niu, Ruilan

    2016-01-01

    We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway. PMID:27579327

  8. NDRG1 functions in LDL receptor trafficking by regulating endosomal recycling and degradation.

    PubMed

    Pietiäinen, Vilja; Vassilev, Boris; Blom, Tomas; Wang, Wei; Nelson, Jessica; Bittman, Robert; Bäck, Nils; Zelcer, Noam; Ikonen, Elina

    2013-09-01

    N-myc downstream-regulated gene 1 (NDRG1) mutations cause Charcot-Marie-Tooth disease type 4D (CMT4D). However, the cellular function of NDRG1 and how it causes CMT4D are poorly understood. We report that NDRG1 silencing in epithelial cells results in decreased uptake of low-density lipoprotein (LDL) due to reduced LDL receptor (LDLR) abundance at the plasma membrane. This is accompanied by the accumulation of LDLR in enlarged EEA1-positive endosomes that contain numerous intraluminal vesicles and sequester ceramide. Concomitantly, LDLR ubiquitylation is increased but its degradation is reduced and ESCRT (endosomal sorting complex required for transport) proteins are downregulated. Co-depletion of IDOL (inducible degrader of the LDLR), which ubiquitylates the LDLR and promotes its degradation, rescues plasma membrane LDLR levels and LDL uptake. In murine oligodendrocytes, Ndrg1 silencing not only results in reduced LDL uptake but also in downregulation of the oligodendrocyte differentiation factor Olig2. Both phenotypes are rescued by co-silencing of Idol, suggesting that ligand uptake through LDLR family members controls oligodendrocyte differentiation. These findings identify NDRG1 as a novel regulator of multivesicular body formation and endosomal LDLR trafficking. The deficiency of functional NDRG1 in CMT4D might impair lipid processing and differentiation of myelinating cells.

  9. Disruption of LDL but not VLDL clearance in autosomal recessive hypercholesterolemia

    PubMed Central

    Jones, Christopher; Garuti, Rita; Michaely, Peter; Li, Wei-Ping; Maeda, Nobuyo; Cohen, Jonathan C.; Herz, Joachim; Hobbs, Helen H.

    2007-01-01

    Genetic defects in LDL clearance result in severe hypercholesterolemia and premature atherosclerosis. Mutations in the LDL receptor (LDLR) cause familial hypercholesterolemia (FH), the most severe form of genetic hypercholesterolemia. A phenocopy of FH, autosomal recessive hypercholesterolemia (ARH), is due to mutations in an adaptor protein involved in LDLR internalization. Despite comparable reductions in LDL clearance rates, plasma LDL levels are substantially lower in ARH than in FH. To determine the metabolic basis for this difference, we examined the synthesis and catabolism of VLDL in murine models of FH (Ldlr–/–) and ARH (Arh–/–). The hyperlipidemic response to a high-sucrose diet was greatly attenuated in Arh–/– mice compared with Ldlr–/– mice despite similar rates of VLDL secretion. The rate of VLDL clearance was significantly higher in Arh–/– mice than in Ldlr–/– mice, suggesting that LDLR-dependent uptake of VLDL is maintained in the absence of ARH. Consistent with these findings, hepatocytes from Arh–/– mice (but not Ldlr–/– mice) internalized β-migrating VLDL (β-VLDL). These results demonstrate that ARH is not required for LDLR-dependent uptake of VLDL by the liver. The preservation of VLDL remnant clearance attenuates the phenotype of ARH and likely contributes to greater responsiveness to statins in ARH compared with FH. PMID:17200716

  10. [The long-term therapy of familial hypercholesterolemia with heparin-induced extracorporeal LDL precipitation].

    PubMed

    Roth, R; Köster, W; Wanner, C; Andre, M; Orth, M; Wieland, H; Schollmeyer, P

    1992-07-24

    The long-term tolerance to and effectiveness of heparin-induced extracorporeal LDL precipitation (HELP) in combination with lipid reducing drugs and diet was tested in six patient (5 males, 1 female; mean age 48 +/- 4 years). Follow-up period was over 50 months, in one patient over 24 months, while one man had a sudden cardiac death 57 weeks after starting treatment. The study was divided into three phases. In phase I (24 months) treatment consisted of HELP and conventional lipid-reducing drugs; in phase II (12 months) of lovastatin (80 mg daily) and cholestyramine (12-24 g daily); and phase III (14 months) of HELP, lovastatin and cholestyramine. In phase I it was possible to lower the pre-treatment level of LDL-cholesterol from 306 +/- 18 mg/dl to 173 +/- 13 mg/dl (43.5%). A similar effect (from 307 +/- 21 mg/dl to 155 +/- 17 mg/dl [-49.5%]) was obtained in phase II. The resumption of HELP reduced the pre-treatment LDL concentration to 136 +/- 9 mg/dl (-55.7%). The various treatment regimens were well tolerated. Biochemical data remained unchanged except for iron loss requiring substitution. Thus combined HELP, lovastatin and ion exchange offer for the first time an effective and reliable means in familial hypercholesterolaemia of clearly reducing long-term the mean LDL cholesterol level below the atherosclerosis threshold of 120 mg/dl.

  11. New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs

    PubMed Central

    Norata, Giuseppe Danilo; Ballantyne, Christie M.; Catapano, Alberico Luigi

    2013-01-01

    Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach. PMID:23509227

  12. Effect of Endomorphins on HUVECs Treated by ox-LDL and Its Related Mechanisms.

    PubMed

    Zhao, Juan; Zhang, Qi; Liu, Jing; Tian, Liming; Huang, Wenhui; Quan, Jinxing; Wang, Jinyang; Xu, Yanjia; Wang, Yunfang; Niu, Ruilan

    2016-01-01

    We found in the present study that treatment with ox-LDL decreased the cell viability and the content of nitric oxide (NO) and the activity of nitric oxide synthase (NOS) as well as eNOS mRNA expression, while increasing the mRNA expression and content of endothelin-1 (ET-1) in human umbilical vein endothelial cells (HUVECs). However, endomorphins EM1/EM2 increased the cell viability and the content of NO and the activity of NOS as well as eNOS mRNA expression, while decreasing the mRNA expression and content of ET-1 compared with ox-LDL alone. Meanwhile, the expressions of JNK and p-JNK were enhanced by ox-LDL while being suppressed by EM1/EM2. The results suggested that EM1 and EM2 can correct the endothelial cell dysfunction induced by ox-LDL and the protective effect may be achieved by affecting the JNK pathway.

  13. Age- and Gender-Related Differences in LDL-Cholesterol Management in Outpatients with Type 2 Diabetes Mellitus

    PubMed Central

    Russo, Giuseppina; Pintaudi, Basilio; Giorda, Carlo; Lucisano, Giuseppe; Nicolucci, Antonio; Cristofaro, Maria Rosaria; Suraci, Concetta; Mulas, Maria Franca; Napoli, Angela; Rossi, Maria Chiara; Manicardi, Valeria

    2015-01-01

    Background. Dyslipidemia contribute to the excess of coronary heart disease (CHD) risk observed in women with type 2 diabetes (T2DM). Low density lipoprotein-cholesterol (LDL-C) is the major target for CHD prevention, and T2DM women seem to reach LDL-C targets less frequently than men. Aim. To explore age- and gender-related differences in LDL-C management in a large sample of outpatients with T2DM. Results. Overall, 415.294 patients (45.3% women) from 236 diabetes centers in Italy were included. Women were older and more obese, with longer diabetes duration, higher total-cholesterol, LDL-C, and HDL-C serum levels compared to men (P < 0.0001). Lipid profile was monitored in ~75% of subjects, women being monitored less frequently than men, irrespective of age. More women did not reach the LDL-C target as compared to men, particularly in the subgroup treated with lipid-lowering medications. The between-genders gap in reaching LDL-C targets increased with age and diabetes duration, favouring men in all groups. Conclusions. LDL-C management is worst in women with T2DM, who are monitored and reach targets less frequently than T2DM men. Similarly to men, they do not receive medications despite high LDL-C. These gender discrepancies increase with age and diabetes duration, exposing older women to higher CHD risk. PMID:25873960

  14. The lipid- and lipoprotein- [LDL-Lp(a)] apheresis techniques. Updating.

    PubMed

    Stefanutti, C; Morozzi, C; Perrone, G; Di Giacomo, S; Vivenzio, A; D'Alessandri, G

    2012-01-01

    Therapeutic plasmapheresis allows the extracorporeal removal of plasmatic lipoproteins (Lipid-apheresis) (LA). It can be non selective (non specific), semi - selective or selective low density lipoprotein-lipoprotein(a) (specific [LDL- Lp(a)] apheresis) (Lipoprotein apheresis, LDLa). The LDL removal rate is a perfect parameter to assess the system efficiency. Plasma-Exchange (PEX) cannot be considered either specific nor, selective. In PEX the whole blood is separated into plasma and its corpuscular components usually through centrifugation or rather filtration. The corpuscular components mixed with albumin solution plus saline (NaCl 0.9%) solution at 20%-25%, are then reinfused to the patient, to substitute the plasma formerly removed. PEX eliminates atherogenic lipoproteins, but also other essential plasma proteins, such as albumin, immunoglobulins, and hemocoagulatory mediators. Cascade filtration (CF) is a method based on plasma separation and removal of plasma proteins through double filtration. During the CF two hollow-fiber filters with pores of different diameter are used to eliminate the plasma components of different weight and molecular diameter. A CF system uses a first polypropylene filter with 0.55 µm diameter pores and a second one of diacetate of cellulose with 0.02 µm pores. The first filter separates the whole blood, and the plasma is then perfused through a second filter which allows the recovery of molecules with a diameter lower than 0.02 µm, and the removal of molecules larger in diameter as apoB100-containing lipoproteins. Since both albumin and immunoglobulins are not removed, or to a negligible extent, plasma-expanders, substitution fluids, and in particular albumin, as occurs in PEX are not needed. CF however, is characterized by lower selectivity since removes also high density lipoprotein (HDL) particles which have an antiatherogenic activity. In the 80's, a variation of Lipid-apheresis has been developed which allows the LDL

  15. Association between LDL-cholesterol lowering genetic variants and risk of type 2 diabetes

    PubMed Central

    Lotta, Luca A.; Sharp, Stephen. J; Burgess, Stephen; Perry, John R. B.; Stewart, Isobel. D; Willems, Sara M.; Luan, Jian’an; Ardanaz, Eva; Arriola, Larraitz; Balkau, Beverley; Boeing, Heiner; Deloukas, Panos; Forouhi, Nita G; Franks, Paul W; Grioni, Sara; Kaaks, Rudolf; Key, Timothy J; Navarro, Carmen; Nilsson, Peter M; Overvad, Kim; Palli, Domenico; Panico, Salvatore; Quirós, Jose-Ramón; Riboli, Elio; Rolandsson, Olov; Sacerdote, Carlotta; Salamanca, Elena C; Slimani, Nadia; Spijkerman, Annemieke MW; Tjonneland, Anne; Tumino, Rosario; van der A, Daphne L; van der Schouw, Yvonne T; McCarthy, Mark I.; Barroso, Inês; O’Rahilly, Stephen; Savage, David. B; Sattar, Naveed; Langenberg, Claudia

    2017-01-01

    Importance Low-density lipoprotein (LDL) cholesterol-lowering alleles in or near NPC1L1 or HMGCR, encoding the respective molecular targets of ezetimibe and statins, have previously been used as proxies to study the efficacy of these lipid-lowering drugs. Alleles near HMGCR are associated with a higher risk of type 2 diabetes, mimicking the increased incidence of new-onset diabetes associated with statin treatment in randomized clinical trials. It is unknown whether alleles near NPC1L1 are also associated with the risk of type 2 diabetes. Objective To investigate whether LDL-lowering alleles in or near NPC1L1 and other genes encoding current or prospective molecular targets of lipid-lowering therapy (i.e. HMGCR, PCSK9, ABCG5/G8, LDLR) are associated with the risk of type 2 diabetes. Design, Setting and Participants The associations with type 2 diabetes and coronary artery disease of LDL-lowering genetic variants were investigated in meta-analyses of genetic association studies. Meta-analyses included 50,775 individuals with type 2 diabetes and 270,269 controls including three studies and 60,801 individuals with coronary artery disease and 123,504 controls from a published meta-analysis. Data collection took place in Europe and the United States between 1991 and 2016. Exposure LDL-lowering alleles in or near NPC1L1, HMGCR, PCSK9, ABCG5/G8, LDLR. Main Outcomes and Measures Odds ratio of type 2 diabetes and coronary artery disease. Results LDL-lowering genetic variants at NPC1L1 were inversely associated with coronary artery disease (odds ratio for a genetically-predicted reduction of 1 mmol/L in LDL cholesterol, 0.61; 95% confidence interval, 0.42-0.88; p=0.008) and directly associated with type 2 diabetes (2.42, 1.70-3.43; p<0.001). The odds ratio of type 2 diabetes for PCSK9 genetic variants was 1.19 (95% confidence interval, 1.02-1.38, p=0.03). For a given reduction in LDL cholesterol, genetic variants were associated with a similar reduction in coronary artery

  16. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling.

    PubMed

    Zhou, Ming-Sheng; Chadipiralla, Kiranmai; Mendez, Armando J; Jaimes, Edgar A; Silverstein, Roy L; Webster, Keith; Raij, Leopoldo

    2013-08-15

    Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36(+)/CD14(+) cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE-/- mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36-/- apoE-/- mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of extended use

  17. Characterization of a family of gamma-ray-induced CHO mutants demonstrates that the ldlA locus is diploid and encodes the low-density lipoprotein receptor

    SciTech Connect

    Sege, R.D.; Kozarsky, K.F.; Krieger, M.

    1986-09-01

    The ldlA locus is one of four Chinese hamster ovary (CHO) cell loci which are known to be required for the synthesis of functional low-density lipoprotein (LDL) receptors. Previous studies have suggested that the ldlA locus is diploid and encodes the LDL receptor. To confirm this assignment, we have isolated a partial genomic clone of the Chinese hamster LDL receptor gene and used this and other nucleic acid and antibody probes to study a family of ldlA mutants isolated after gamma-irradiation. Our analysis suggests that there are two LDL receptor alleles in wild-type CHO cells. Each of the three mutants isolated after gamma-irradiation had detectable deletions affecting one of the two LDL receptor alleles. One of the mutants also had a disruption of the remaining allele, resulting in the synthesis of an abnormal receptor precursor which was not subject to Golgi-associated posttranslational glycoprotein processing. The correlation of changes in the expression, structure, and function of LDL receptors with deletions in the LDL receptor genes in these mutants directly demonstrated that the ldlA locus in CHO cells is diploid and encodes the LDL receptor. In addition, our analysis suggests that CHO cells in culture may contain a partial LDL receptor pseudogene.

  18. Characterization of a family of gamma-ray-induced CHO mutants demonstrates that the ldlA locus is diploid and encodes the low-density lipoprotein receptor.

    PubMed

    Sege, R D; Kozarsky, K F; Krieger, M

    1986-09-01

    The ldlA locus is one of four Chinese hamster ovary (CHO) cell loci which are known to be required for the synthesis of functional low-density lipoprotein (LDL) receptors. Previous studies have suggested that the ldlA locus is diploid and encodes the LDL receptor. To confirm this assignment, we have isolated a partial genomic clone of the Chinese hamster LDL receptor gene and used this and other nucleic acid and antibody probes to study a family of ldlA mutants isolated after gamma-irradiation. Our analysis suggests that there are two LDL receptor alleles in wild-type CHO cells. Each of the three mutants isolated after gamma-irradiation had detectable deletions affecting one of the two LDL receptor alleles. One of the mutants also had a disruption of the remaining allele, resulting in the synthesis of an abnormal receptor precursor which was not subject to Golgi-associated posttranslational glycoprotein processing. The correlation of changes in the expression, structure, and function of LDL receptors with deletions in the LDL receptor genes in these mutants directly demonstrated that the ldlA locus in CHO cells is diploid and encodes the LDL receptor. In addition, our analysis suggests that CHO cells in culture may contain a partial LDL receptor pseudogene.

  19. Associations of Circulating Oxidized LDL and Conventional Biomarkers of Cardiovascular Disease in a Cross-Sectional Study of the Navajo Population.

    PubMed

    Harmon, Molly E; Campen, Matthew J; Miller, Curtis; Shuey, Chris; Cajero, Miranda; Lucas, Selita; Pacheco, Bernadette; Erdei, Esther; Ramone, Sandy; Nez, Teddy; Lewis, Johnnye

    2016-01-01

    The prevalences of cardiovascular disease (CVD) and type 2 diabetes (T2D) have increased among the Navajo Native American community in recent decades. Oxidized low-density lipoprotein (oxLDL) is a novel CVD biomarker that has never been assessed in the Navajo population. We examined the relationship of oxLDL to conventional CVD and T2D risk factors and biomarkers in a cross-sectional population of Navajo participants. This cross-sectional study included 252 participants from 20 Navajo communities from the Diné Network for Environmental Health Project. Plasma samples were tested for oxLDL levels by a sandwich enzyme-linked immunosorbent assay. Univariate and multivariate analyses were used to determine the relationship of oxLDL and oxidized- to non-oxidized lipoprotein ratios to glycated hemoglobin (HbA1c), C-reactive protein (CRP), interleukin 6 (IL6) and demographic and health variables. Type 2 diabetes, hypertension and obesity are very prevalent in this Navajo population. HbA1c, CRP, body mass index (BMI), high-density lipoprotein, and triglycerides were at levels that may increase risk for CVD and T2D. Median oxLDL level was 47 (36.8-57) U/L. Correlational analysis showed that although oxLDL alone was not associated with HbA1c, oxLDL/HDL, oxLDL/LDL and CRP were significantly associated with HbA1c and glucose. OxLDL, oxLDL/HDL and oxLDL/LDL were significantly associated with CRP. Multivariate analysis showed that triglycerides were a common and strong predictor of oxLDL, oxLDL/HDL and oxLDL/LDL. OxLDL was trended with HbA1c and glucose but did not reach significance, however, HbA1c was an independent predictor of OxLDL/HDL. CRP trended with oxLDL/HDL and was a weak predictor of oxLDL/LDL. This Navajo subset appears to have oxLDL levels comparable to subjects without evidence of CVD reported in other studies. The high prevalence of T2D, hypertension and obesity along with abnormal levels of other biomarkers including HbA1c indicate that the Navajo population has

  20. Protein Inhibitor of Activated STAT3 Suppresses Oxidized LDL-induced Cell Responses during Atherosclerosis in Apolipoprotein E-deficient Mice

    PubMed Central

    Wang, Rong; Zhang, Yanjin; Xu, Liran; Lin, Yan; Yang, Xiaofeng; Bai, Liang; Chen, Yulong; Zhao, Sihai; Fan, Jianglin; Cheng, Xianwu; Liu, Enqi

    2016-01-01

    Atherosclerosis is a serious public health concern. Excessive inflammatory responses of vascular cells are considered a pivotal pathogenesis mechanism underlying atherosclerosis development. It is known that Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) signalling plays an important role in atherosclerosis progression. Protein inhibitor of activated STAT3 (PIAS3) is the key negative regulator of JAK/STAT3 signalling. However, its effect on atherogenesis is unknown. Here, we observed that PIAS3 levels are reduced in atherosclerotic lesions and that PIAS3 expression decreases in conjunction with increases in interleukin-6 expression and atherosclerosis severity. Oxidized low-density lipoprotein (ox-LDL), an atherogenic stimulus, reduced PIAS3 expression, an effect that may be attributed to nitric oxide synthesis upregulation. In turn, PIAS3 overexpression effectively suppressed ox-LDL-induced inflammation, lipid accumulation and vascular smooth muscle cell proliferation. These results indicate that PIAS3 is a critical repressor of atherosclerosis progression. The findings of this study have contributed to our understanding on the pathogenesis of atherosclerosis and have provided us with a potential target through which we can inhibit atherosclerosis-related cellular responses. PMID:27845432

  1. Dominant role of local dipolar interactions in phosphate binding to a receptor cleft with an electronegative charge surface: equilibrium, kinetic, and crystallographic studies.

    PubMed

    Ledvina, P S; Tsai, A L; Wang, Z; Koehl, E; Quiocho, F A

    1998-12-01

    Stringent specificity and complementarity between the receptor, a periplasmic phosphate-binding protein (PBP) with a two-domain structure, and the completely buried and dehydrated phosphate are achieved by hydrogen bonding or dipolar interactions. We recently found that the surface charge potential of the cleft between the two domains that contains the anion binding site is intensely electronegative. This novel finding prompted the study reported here of the effect of ionic strength on the equilibrium and rapid kinetics of phosphate binding. To facilitate this study, Ala197, located on the edge of the cleft, was replaced by a Trp residue (A197W PBP) to generate a fluorescence reporter group. The A197W PBP-phosphate complex retains wild-type Kd and X-ray structure beyond the replacement residue. The Kd (0.18 microM) at no salt is increased by 20-fold at greater than 0.30 M NaCl. Stopped-flow fluorescence kinetic studies indicate a two-step binding process: (1) The phosphate (L) binds, at near diffusion-controlled rate, to the open cleft form (Po) of PBP to produce an intermediate, PoL. This rate decreases with increasing ionic strength. (2) The intermediate isomerizes to the closed-conformation form, PcL. The results indicate that the high specificity, affinity, and rate of phosphate binding are not influenced by the noncomplementary electronegative surface potential of the cleft. That binding depends almost entirely on local dipolar interactions with the receptor has important ramification in electrostatic interactions in protein structures and in ligand recognition.

  2. Dominant role of local dipolar interactions in phosphate binding to a receptor cleft with an electronegative charge surface: equilibrium, kinetic, and crystallographic studies.

    PubMed Central

    Ledvina, P. S.; Tsai, A. L.; Wang, Z.; Koehl, E.; Quiocho, F. A.

    1998-01-01

    Stringent specificity and complementarity between the receptor, a periplasmic phosphate-binding protein (PBP) with a two-domain structure, and the completely buried and dehydrated phosphate are achieved by hydrogen bonding or dipolar interactions. We recently found that the surface charge potential of the cleft between the two domains that contains the anion binding site is intensely electronegative. This novel finding prompted the study reported here of the effect of ionic strength on the equilibrium and rapid kinetics of phosphate binding. To facilitate this study, Ala197, located on the edge of the cleft, was replaced by a Trp residue (A197W PBP) to generate a fluorescence reporter group. The A197W PBP-phosphate complex retains wild-type Kd and X-ray structure beyond the replacement residue. The Kd (0.18 microM) at no salt is increased by 20-fold at greater than 0.30 M NaCl. Stopped-flow fluorescence kinetic studies indicate a two-step binding process: (1) The phosphate (L) binds, at near diffusion-controlled rate, to the open cleft form (Po) of PBP to produce an intermediate, PoL. This rate decreases with increasing ionic strength. (2) The intermediate isomerizes to the closed-conformation form, PcL. The results indicate that the high specificity, affinity, and rate of phosphate binding are not influenced by the noncomplementary electronegative surface potential of the cleft. That binding depends almost entirely on local dipolar interactions with the receptor has important ramification in electrostatic interactions in protein structures and in ligand recognition. PMID:9865949

  3. Differential effects of the changes of LDL cholesterol and systolic blood pressure on the risk of carotid artery atherosclerosis

    PubMed Central

    2012-01-01

    Background The effects of baseline and changes in blood pressure and low density lipoprotein (LDL) cholesterol on the carotid intima media thickness (IMT) have not been well documented. Methods A total of 2572 adults (mean age 53.8 years, 54.6% women) in a Taiwanese community undertook three blood pressure and LDL cholesterol examinations over 6 years. Latent growth curve modeling was used to investigate the effects of baseline and change in blood pressure and LDL cholesterol on IMT. Results Greater baseline LDL and blood pressure were associated with an increase in IMT (0.005 ± 0.002 mm per 1 mg/dL [p = 0.006] and 0.041 ± 0.004 mm mmHg [p <0.0001], respectively. Change in blood pressure was associated with a significant increase in IMT (0.047±0.016, P = 0.004), whilst the association between change in LDL and change in IMT was not statistically significant (0.008±0.006, P = 0.20). Conclusions Carotid IMT was associated with baseline blood pressure and LDL cholesterol, yet only changes of blood pressure, not LDL cholesterol, were related to carotid IMT during the 6-year observation. PMID:22900906

  4. Low LDL cholesterol and increased risk of Parkinson's disease: prospective results from Honolulu-Asia Aging Study.

    PubMed

    Huang, Xuemei; Abbott, Robert D; Petrovitch, Helen; Mailman, Richard B; Ross, G Webster

    2008-05-15

    Low-density lipoprotein cholesterol (LDL-C) levels are suggested to be associated inversely with Parkinson's disease (PD). To test the hypothesis that LDL-C levels may increase PD risk, we studied a prospective cohort of 3,233 men (Honolulu-Asia Aging Study) for whom the LDL-C from fasting lipid profiles was obtained during 1991 to 1993. The cohort was followed longitudinally until 2001 for incident Parkinson's cases. During follow-up, 41 men developed PD (18.4/10,000 person-years). Although the incidence of PD increased with decreasing LDL-C in a dose-dependent manner, the association was only significant for men aged 71 to 75 years. In the latter group, risk of PD declined from 38.5/10,000 person-years in men with LDL-C levels <80 mg/dl to less than 9/10,000 person-years for concentrations that were > or =140 mg/dl. After adjustment for age, smoking, coffee intake, and other factors, the relative odds of PD for men at the 80th versus the 20th percentile of LDL-C (135 vs. 85 mg/dl) was 0.4 (95% confidence interval: 0.2, 0.9). This prospective study supports the hypothesis that low LDL-C is associated with an increased risk of PD. Although confirmation is required, the underlying mechanisms may be useful in understanding key aspects of PD.

  5. Oxidized LDL binding to LOX-1 upregulates VEGF expression in cultured bovine chondrocytes through activation of PPAR-{gamma}

    SciTech Connect

    Kanata, Sohya; Akagi, Masao . E-mail: makagi@med.kindai.ac.jp; Nishimura, Shunji; Hayakawa, Sumio; Yoshida, Kohji; Sawamura, Tatsuya; Munakata, Hiroshi; Hamanishi, Chiaki

    2006-09-29

    It has been reported that vascular endothelial growth factor (VEGF) and its receptors play an important role in the destruction of articular cartilage in osteoarthritis through increased production of matrix metalloproteinases. We investigated whether the oxidized low-density lipoprotein (ox-LDL) binding to lectin-like ox-LDL receptor-1 (LOX-1) upregulates VEGF expression in cultured bovine articular chondrocytes (BACs). Ox-LDL markedly increased VEGF mRNA expression and protein release in time- and dose-dependent manners, which was significantly suppressed by anti-LOX-1 antibody pretreatment. Activation of peroxisome proliferator-activated receptor (PPAR)-{gamma} was evident in BACs with ox-LDL addition and was attenuated by anti-LOX-1 antibody. The specific PPAR-{gamma} inhibitor GW9662 suppressed ox-LDL-induced VEGF expression. These results suggest that the ox-LDL/LOX-1 system upregulates VEGF expression in articular cartilage, at least in part, through activation of PPAR-{gamma} and supports the hypothesis that ox-LDL is involved in cartilage degradation via LOX-1.

  6. A Prospective Observational Survey on the Long-Term Effect of LDL Apheresis on Drug-Resistant Nephrotic Syndrome

    PubMed Central

    Muso, Eri; Mune, Masatoshi; Hirano, Tsutomu; Hattori, Motoshi; Kimura, Kenjiro; Watanabe, Tsuyoshi; Yokoyama, Hitoshi; Sato, Hiroshi; Uchida, Shunya; Wada, Takashi; Shoji, Tetsuo; Takemura, Tsukasa; Yuzawa, Yukio; Ogahara, Satoru; Sugiyama, Satoshi; Iino, Yasuhiko; Sakai, Soichi; Ogura, Yousuke; Yukawa, Susumu; Nishizawa, Yoshiki; Yorioka, Noriaki; Imai, Enyu; Matsuo, Seiichi; Saito, Takao

    2015-01-01

    Background/Aims LDL apheresis (LDL-A) is used for drug-resistant nephrotic syndrome (NS) as an alternative therapy to induce remission by improvement of hyperlipidemia. Several clinical studies have suggested the efficacy of LDL-A for refractory NS, but the level of evidence remains insufficient. A multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was conducted to evaluate its clinical efficacy with high-level evidence. Methods Patients with NS who showed resistance to primary medication for at least 4 weeks were prospectively recruited to the study and treated with LDL-A. The long-term outcome was evaluated based on the rate of remission of NS 2 years after treatment. Factors affecting the outcome were also examined. Results A total of 58 refractory NS patients from 40 facilities were recruited and enrolled as subjects of the POLARIS study. Of the 44 subjects followed for 2 years, 21 (47.7%) showed remission of NS based on a urinary protein (UP) level <1.0 g/day. The UP level immediately after LDL-A and the rates of improvement of UP, serum albumin, serum creatinine, eGFR, and total and LDL cholesterol after the treatment session significantly affected the outcome. Conclusions Almost half of the cases of drug-resistant NS showed remission 2 years after LDL-A. Improvement of nephrotic parameters at termination of the LDL-A treatment was a predictor of a favorable outcome. PMID:26557843

  7. The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton.

    PubMed

    Yao, Wenjuan; Huang, Lei; Sun, Qinju; Yang, Lifeng; Tang, Lian; Meng, Guoliang; Xu, Xiaole; Zhang, Wei

    2016-10-01

    Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively.

  8. Effects of magnetic field and Hall current to the blood velocity and LDL transfer

    NASA Astrophysics Data System (ADS)

    Abdullah, I.; Naser, N.; Talib, A. H.; Mahali, S.

    2015-09-01

    The magnetic field and Hall current effects have been considered on blood velocity and concentration of low-density lipoprotein (LDL). It is important to observe those effects to the flowing blood in a stenosed artery. The analysis from the obtained results may be useful to some clinical procedures, such as MRI, where the radiologists may have more information in the investigations before cardiac operations could be done. In this study, the uniform magnetic field and Hall current are applied to the Newtonian blood flow through an artery having a cosine-shaped stenosis. The governing equations are coupled with mass transfer and solved employing a finite difference Marker and Cell (MAC) method with an appropriate initial and boundary conditions. The graphical results of velocity profiles and LDL concentration are presented in this paper and the results show that the velocity increases and concentration decreases as Hall parameter increased.

  9. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

    PubMed Central

    Postmus, Iris; Trompet, Stella; Deshmukh, Harshal A.; Barnes, Michael R.; Li, Xiaohui; Warren, Helen R.; Chasman, Daniel I.; Zhou, Kaixin; Arsenault, Benoit J.; Donnelly, Louise A.; Wiggins, Kerri L.; Avery, Christy L.; Griffin, Paula; Feng, QiPing; Taylor, Kent D.; Li, Guo; Evans, Daniel S.; Smith, Albert V.; de Keyser, Catherine E.; Johnson, Andrew D.; de Craen, Anton J. M.; Stott, David J.; Buckley, Brendan M.; Ford, Ian; Westendorp, Rudi G. J.; Eline Slagboom, P.; Sattar, Naveed; Munroe, Patricia B.; Sever, Peter; Poulter, Neil; Stanton, Alice; Shields, Denis C.; O’Brien, Eoin; Shaw-Hawkins, Sue; Ida Chen, Y.-D.; Nickerson, Deborah A.; Smith, Joshua D.; Pierre Dubé, Marie; Matthijs Boekholdt, S.; Kees Hovingh, G.; Kastelein, John J. P.; McKeigue, Paul M.; Betteridge, John; Neil, Andrew; Durrington, Paul N.; Doney, Alex; Carr, Fiona; Morris, Andrew; McCarthy, Mark I.; Groop, Leif; Ahlqvist, Emma; Bis, Joshua C.; Rice, Kenneth; Smith, Nicholas L.; Lumley, Thomas; Whitsel, Eric A.; Stürmer, Til; Boerwinkle, Eric; Ngwa, Julius S.; O’Donnell, Christopher J.; Vasan, Ramachandran S.; Wei, Wei-Qi; Wilke, Russell A.; Liu, Ching-Ti; Sun, Fangui; Guo, Xiuqing; Heckbert, Susan R; Post, Wendy; Sotoodehnia, Nona; Arnold, Alice M.; Stafford, Jeanette M.; Ding, Jingzhong; Herrington, David M.; Kritchevsky, Stephen B.; Eiriksdottir, Gudny; Launer, Leonore J.; Harris, Tamara B.; Chu, Audrey Y.; Giulianini, Franco; MacFadyen, Jean G.; Barratt, Bryan J.; Nyberg, Fredrik; Stricker, Bruno H.; Uitterlinden, André G.; Hofman, Albert; Rivadeneira, Fernando; Emilsson, Valur; Franco, Oscar H.; Ridker, Paul M.; Gudnason, Vilmundur; Liu, Yongmei; Denny, Joshua C.; Ballantyne, Christie M.; Rotter, Jerome I.; Adrienne Cupples, L.; Psaty, Bruce M.; Palmer, Colin N. A.; Tardif, Jean-Claude; Colhoun, Helen M.; Hitman, Graham; Krauss, Ronald M.; Wouter Jukema, J; Caulfield, Mark J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N. A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C. A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; McCarthy, Mark I.; Spencer, Chris C. A.

    2014-01-01

    Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response. PMID:25350695

  10. Investigation of singlet oxygen generation in Vit C-Cu2+ -LDL system by chemiluminescence method

    NASA Astrophysics Data System (ADS)

    Wang, Juan; Xing, Da; Tan, Shici; Tang, Yonghong; He, Yonghong

    2002-04-01

    In this study, by chemiluminescence method using a Cypridina luciferin analog, 2-methyl-6-(p-methoxyphenyl)-3,7- dihydroimidazo[1,2-a]pyrazin-3-one (MCLA), as a selective and sensitive chemiluminescence probe, singlet oxygen (1O2) formation was observed in the vit C- LDL-Cu2+ reaction system. Another experimental evidence for the generation of 1O2 was the quenching effect of sodium azide (NaN3) on vit C-induced chemiluminescence in the reaction mixture of LDL- Cu2+-MCLA. Analysis based on the experimental results indicated the plausible reaction mechanism is that vit C converts Cu2+ to its reduced state and vit C becomes vit C radical itself, thereby stimulating the formation of peroxyl radicals, and bimolecular reaction of peroxyl radicals results in 1O2 production in the above systems.

  11. Lipoprotein lipase, LDL receptors and apo-lipoproteins in human fetal membranes at term.

    PubMed

    Huter, O; Wolf, H J; Schnetzer, A; Pfaller, K

    1997-11-01

    Ultrastructurally, all cells of human fetal membranes strongly exhibit a large amount of lipid deposits throughout pregnancy. Their origin and function is still unknown. The aim of this study was to investigate the localization of key components of lipid metabolism in this tissue. Using immunohistochemical techniques, the distribution of lipoprotein lipase (LPL), low density lipoprotein receptors (LDL receptors), and apo-lipoprotein B and E was investigated in 20 human fetal membranes at term. In addition, electron microscopy was used to study the intracellular localization of lipoprotein-sized particles. Amnionic epithelium and trophoblast cells reacted strongly for LPL. LDL receptors and apo-lipoproteins were present in amnionic epithelium and fibroblasts of the amnion. In none of the investigated cells were lipoprotein-sized particles identified. Similar results were obtained in all 20 cases. The findings indicate that lipoprotein from the amniotic fluid or from the maternal circulation may serve as substrate for lipids in human fetal membranes.

  12. Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio.

    PubMed Central

    Navab, M; Hama-Levy, S; Van Lenten, B J; Fonarow, G C; Cardinez, C J; Castellani, L W; Brennan, M L; Lusis, A J; Fogelman, A M; La Du, B N

    1997-01-01

    We have examined the effects of mildly oxidized LDL and atherosclerosis on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity decreased by 52%, and apoJ levels increased 2.8-fold in fatty streak susceptible mice, C57BL/6J (BL/6), but not in fatty streak resistant mice, C3H/HeJ (C3H). Plasma PON activity was also significantly decreased, and apoJ levels were markedly increased in apolipoprotein E knockout mice on the chow diet, resulting in a 9.2-fold increase in the apoJ/PON ratio as compared to controls. Furthermore, a dramatic increase in the apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockout mice when they were fed a 0.15%-cholesterol-enriched diet. Injection of mildly oxidized LDL (but not native LDL) into BL/6 mice (but not in C3H mice) on a chow diet resulted in a 59% decrease in PON activity (P < 0.01) and a 3.6-fold increase in apoJ levels (P < 0.01). When an acute phase reaction was induced in rabbits, or the rabbits were placed on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-fold and 2.8-fold, respectively. Treatment of HepG2 cells in culture with mildly oxidized LDL (but not native LDL) resulted in reduced mRNA levels for PON (3.0-fold decrease) and increased mRNA levels for apoJ (2.0-fold increase). In normolipidemic patients with angiographically documented coronary artery disease who did not have diabetes and were not on lipid-lowering medication (n = 14), the total cholesterol/HDL cholesterol ratio was 3.1+/-0.9 as compared to 2.9+/-0.4 in the controls (n = 19). This difference was not statistically significant. In contrast, the apoJ/PON ratio was 3.0+/-0.4 in the patients compared to 0.72+/-0.2 in the controls (P < 0.009). In a subset of these normolipidemic patients (n = 5), the PON activity was low (48+/-6.6 versus 98+/-17 U/ml for controls; P < 0.009), despite similar normal HDL levels, and the HDL from these patients failed to

  13. Effects of a very high saturated fat diet on LDL particles in adults with atherogenic dyslipidemia: A randomized controlled trial

    PubMed Central

    Chiu, Sally; Williams, Paul T.

    2017-01-01

    Background Previous studies have shown that increases in LDL-cholesterol resulting from substitution of dietary saturated fat for carbohydrate or unsaturated fat are due primarily to increases in large cholesterol-enriched LDL, with minimal changes in small, dense LDL particles and apolipoprotein B. However, individuals can differ by their LDL particle distribution, and it is possible that this may influence LDL subclass response. Objective The objective of this study was to test whether the reported effects of saturated fat apply to individuals with atherogenic dyslipidemia as characterized by a preponderance of small LDL particles (LDL phenotype B). Methods Fifty-three phenotype B men and postmenopausal women consumed a baseline diet (55%E carbohydrate, 15%E protein, 30%E fat, 8%E saturated fat) for 3 weeks, after which they were randomized to either a moderate carbohydrate, very high saturated fat diet (HSF; 39%E carbohydrate, 25%E protein, 36%E fat, 18%E saturated fat) or low saturated fat diet (LSF; 37%E carbohydrate, 25%E protein, 37%E fat, 9%E saturated fat) for 3 weeks. Results Compared to the LSF diet, consumption of the HSF diet resulted in significantly greater increases from baseline (% change; 95% CI) in plasma concentrations of apolipoprotein B (HSF vs. LSF: 9.5; 3.6 to 15.7 vs. -6.8; -11.7 to -1.76; p = 0.0003) and medium (8.8; -1.3 to 20.0 vs. -7.3; -15.7 to 2.0; p = 0.03), small (6.1; -10.3 to 25.6 vs. -20.8; -32.8 to -6.7; p = 0.02), and total LDL (3.6; -3.2 to 11.0 vs. -7.9; -13.9 to -1.5; p = 0.03) particles, with no differences in change of large and very small LDL concentrations. As expected, total-cholesterol (11.0; 6.5 to 15.7 vs. -5.7; -9.4 to -1.8; p<0.0001) and LDL-cholesterol (16.7; 7.9 to 26.2 vs. -8.7; -15.4 to -1.4; p = 0.0001) also increased with increased saturated fat intake. Conclusions Because medium and small LDL particles are more highly associated with cardiovascular disease than are larger LDL, the present results suggest

  14. Practical aspects of direct adsorption of lipoproteins from whole blood by DALI LDL-apheresis.

    PubMed

    Bosch, Thomas

    2004-10-01

    Direct adsorption of lipoproteins (DALI) from whole blood is the first LDL-hemoperfusion procedure. The present paper addresses practical questions of DALI apheresis in order to optimise DALI therapy in sometimes critically ill coronary patients. The reduction of LDL and Lp(a) by DALI can be optimised by increasing the treated blood volume and the DALI adsorber volume. Hypotension (1.2% of sessions) may be minimised by fluid intake before the session, isovolemic connection of the patient to the ECC, reduced blood flow and low ACD-A ratio. Hypocalcemia may be avoided by low citrate anticoagulation (1:40) and reduced blood flow. Bradykinin release peaks at ca. 1000 ml of treated blood volume and may cause Quincke edema (tight throat), hypotension and flush. Reduction of the blood flow rate and decrease of citrate admixture as well as administration of iv. calcium may be helpful. While ACE inhibitors are contraindicated in DALI patients, sartans may be used without problems. Some "intrinsic" PTT increase is caused by adsorption of coagulation factors; undue PTT prolongations after DALI may be avoided by reduction of the heparin dosage during priming and treatment. In patients prone to alkalosis and hypokalemia, a reduction of the ACD-A ratio is recommended. Rises of adsorber inlet pressure may be due to insufficient anticoagulation and adsorber clotting or malfunctioning of the venous access. Rinsing of the adsorber with saline, administration of a heparin bolus and increase of the citrate admixture as well as a rinse and/or repositioning of the venous access are helpful measures. If these basic rules are followed, DALI LDL-apheresis is a safe, efficient, rapid and user-friendly LDL-apheresis procedure as evidenced by more than 80,000 DALI sessions successfully performed to date.

  15. Antioxidant activity of various teas against free radicals and LDL oxidation.

    PubMed

    Ohmori, Reiko; Iwamoto, Tamami; Tago, Motomi; Takeo, Tadakazu; Unno, Tomonori; Itakura, Hiroshige; Kondo, Kazuo

    2005-08-01

    Tea is a widely consumed beverage throughout the world. We assessed the antioxidant activity of six teas, including the aqueous extracts of green tea and oolong tea (Camellia sinensis), tochu (Eucommia ulmoides), Gymnema sylvestre, Japanese mugwort (Artemisia princeps), and barley (Hordeum vulgare), against 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals and LDL oxidation, and examined the association of LDL oxidizability with the plasma catechin levels in 10 healthy volunteers with a single dose of 5 g green tea powder. In vitro, the inhibitory effects of DPPH radicals and LDL oxidation were found to be strongest in the extract of green tea and weakest in that of barley. After the ingestion of green tea powder, the lag time increased from basal 52.2 +/- 4.1 to 60.3 +/- 4.2 min at 1 h and 59.5 +/- 4.1 min at 2 h, and then returned to the baseline lag time (51.9 +/- 1.4 at 4 h and 52.1 +/- 4.7 min at 6 h). Regarding the plasma catechin levels, epigallocatechingallate and epicatechingallate significantly increased from basal 3.7 +/- 1.3 and 0.8 +/- 0.8 ng/mL to 65.7 +/- 11.6 and 54.6 +/- 12.6 ng/mL at 1 h, and 74.4 +/- 18.6 and 49.4 +/- 7.1 ng/mL at 2 h, respectively. Green tea therefore showed the strongest antioxidant activity among the six different teas, and the inhibitory effects of green tea on LDL oxidation depended on the plasma catechin levels.

  16. HMGCR rs17671591 SNP Determines Lower Plasma LDL-C after Atorvastatin Therapy in Chilean Individuals.

    PubMed

    Cuevas, Alejandro; Fernández, César; Ferrada, Luis; Zambrano, Tomás; Rosales, Alexy; Saavedra, Nicolás; Salazar, Luis A

    2016-04-01

    Lipid-lowering response to statin therapy shows large interindividual variability. At a genome-wide significance level, single nucleotide polymorphisms (SNPs) in PCSK9 and HMGCR have been implicated in this differential response. However, the influence of these variants is uncertain in the Chilean population. Hence, we aimed to evaluate the contribution of PCSK9 rs7552841 and HMGCR rs17671591 SNPs as genetic determinants of atorvastatin response in Chilean hypercholesterolaemic individuals. One hundred and one hypercholesterolaemic patients received atorvastatin 10 mg/day for 4 weeks. Plasma lipid profile (TC, HDL-C, LDL-C and TG) was determined before and after statin treatment, and SNPs were identified by allelic discrimination using TaqMan(®) SNP Genotyping Assays. Adjusted univariate and multivariate analyses' models were used for statistical analyses, and a p-value <0.05 was considered significant. From baseline (week 0) to the study end-point (week 4), significant reductions were observed in plasma TC, LDL-C and TG (p < 0.001), while HDL-C levels were increased (p < 0.001). Multivariate analysis showed no association between lipid levels and atorvastatin therapy for the PCSK9 variant. However, the HMGCR rs17671591 T allele contributed to basal HDL-C concentration variability along with a higher increase in this lipid fraction after statin medication. In addition, this allele determined greater plasma LDL-C reductions after therapy with atorvastatin. Our data suggest that the HMGCR rs17671591 polymorphism can constitute a genetic marker of lower plasma LDL-C and enhanced HDL-C concentration after atorvastatin therapy in the Chilean population.

  17. Changes in Lipids and Lipoproteins after Selective LDL Apheresis (7-Year Experience)

    PubMed Central

    Kolovou, Genovefa; Hatzigeorgiou, Georgios; Mihas, Constantinos; Gontoras, Nikos; Litras, Panagiotis; Devekousos, Dimitris; Kontodima, Panagiota; Sorontila, Constantina; Bilianou, Helen; Mavrogeni, Sophie

    2012-01-01

    Background. The aim of the study was to investigate the changes in plasma lipids and lipoproteins and the cardiovascular events after selective LDL apheresis. Methods and Results. Two pediatric patients with familial hypercholesterolemia aged 11 and 13 years and 19 dyslipidemic adults aged 41 ± 14 years underwent direct adsorption of lipoproteins (DALI) sessions. The mean follow-up period was 47 ± 23 months. The total cholesterol (TC) values before and after treatment were 8.2 ± 2.2 and 3.1 ± 1.6 mmol/l (318 ± 86 and 122 ± 62 mg/dL), respectively. The interval mean of TC was 6.9 ± 1.9 mmol/l (268 ± 75 mg/dL). The LDL cholesterol concentrations before and after treatment were 6.6 ± 2.1 and 1.7 ± 1.1 mmol/l, (256 ± 82 mg/dL and 65 ± 41 mg/dL), respectively. The percentage of acute LDL cholesterol reduction was 75 ± 11%. Cardiovascular events were observed in seven patients. The average annual event rate was 5.51%. Conclusion. LDL apheresis is a very important therapeutic tool in managing patients at high risk for premature CAD or with aggressive CAD, despite adequate medical treatment. PMID:22315677

  18. Observational study of lipid profile and LDL particle size in patients with metabolic syndrome

    PubMed Central

    2011-01-01

    Background The atherogenic lipoprotein phenotype is characterized by an increase in plasma triglycerides, a decrease in high-density lipoprotein cholesterol (HDLc), and the prevalence of small, dense-low density lipoprotein cholesterol (LDLc) particles. The aim of this study was to establish the importance of LDL particle size measurement by gender in a group of patients with Metabolic Syndrome (MS) attending at a Cardiovascular Risk Unit in Primary Care and their classification into phenotypes. Subjects and methods One hundred eighty-five patients (93 men and 92 women) from several areas in the South of Spain, for a period of one year in a health centre were studied. Laboratory parameters included plasma lipids, lipoproteins, low-density lipoprotein size and several atherogenic rates were determinated. Results We found differences by gender between anthropometric parameters, blood pressure and glucose measures by MS status. Lipid profile was different in our two study groups, and gender differences in these parameters within each group were also remarkable, in HDLc and Apo A-I values. According to LDL particle size, we found males had smaller size than females, and patients with MS had also smaller than those without MS. We observed inverse relationship between LDL particle size and triglycerides in patients with and without MS, and the same relationship between all atherogenic rates in non-MS patients. When we considered our population in two classes of phenotypes, lipid profile was worse in phenotype B. Conclusion In conclusion, we consider worthy the measurement of LDL particle size due to its relationship with lipid profile and cardiovascular risk. PMID:21936888

  19. Insoluble carob fiber rich in polyphenols lowers total and LDL cholesterol in hypercholesterolemic sujects.

    PubMed

    Ruiz-Roso, Baltasar; Quintela, José C; de la Fuente, Ester; Haya, Javier; Pérez-Olleros, Lourdes

    2010-03-01

    Recently, polyphenols have been found to affect blood lipids in animals in a similar manner as soluble dietary fibre. The aim was to assess whether an insoluble dietary fiber very rich in polyphenols has a beneficial effect on serum lipids in humans. In a double-blind randomized placebo-controlled clinical study with parallel arms, 88 volunteers with hypercholesterolemia were randomly assigned to consume daily either, fiber with insoluble 84% polyphenols 4 g twice a day (n = 43) or placebo (n = 45). Serum total, LDL and HDL cholesterol and triglycerides were assessed at baseline and after 4 weeks. The insoluble polyphenols consumption reduced the total cholesterol by 17.8 +/- 6.1% (p < 0.05), LDL cholesterol by 22.5 +/- 8.9% (p < 0.001), LDL: HDL cholesterol ratio by 26.2 +/- 14.3% (p < 0.001) and triglycerides by 16.3 +/- 23.4% (p < 0.05) at the end of the study compared with baseline. No significant differences were found during the study time in the placebo group for the lipid profile. The consumption of fiber very rich in insoluble polyphenols shows beneficial effects on human blood lipid profile and may be effective in prevention and treatment of hyperlipemia.

  20. Near Infrared Fluorescence (NIRF) Molecular Imaging of Oxidized LDL with an Autoantibody in Experimental Atherosclerosis

    PubMed Central

    Khamis, Ramzi Y; Woollard, Kevin J.; Hyde, Gareth D.; Boyle, Joseph J; Bicknell, Colin; Chang, Shang-Hung; Malik, Talat H; Hara, Tetsuya; Mauskapf, Adam; Granger, David W; Johnson, Jason L.; Ntziachristos, Vasilis; Matthews, Paul M; Jaffer, Farouc A; Haskard, Dorian O

    2016-01-01

    We aimed to develop a quantitative antibody-based near infrared fluorescence (NIRF) approach for the imaging of oxidized LDL in atherosclerosis. LO1, a well- characterized monoclonal autoantibody that reacts with malondialdehyde-conjugated LDL, was labeled with a NIRF dye to yield LO1-750. LO1-750 specifically identified necrotic core in ex vivo human coronary lesions. Injection of LO1-750 into high fat (HF) fed atherosclerotic Ldlr−/− mice led to specific focal localization within the aortic arch and its branches, as detected by fluorescence molecular tomography (FMT) combined with micro-computed tomography (CT). Ex vivo confocal microscopy confirmed LO1-750 subendothelial localization of LO1-750 at sites of atherosclerosis, in the vicinity of macrophages. When compared with a NIRF reporter of MMP activity (MMPSense-645-FAST), both probes produced statistically significant increases in NIRF signal in the Ldlr−/− model in relation to duration of HF diet. Upon withdrawing the HF diet, the reduction in oxLDL accumulation, as demonstrated with LO1-750, was less marked than the effect seen on MMP activity. In the rabbit, in vivo injected LO1-750 localization was successfully imaged ex vivo in aortic lesions with a customised intra-arterial NIRF detection catheter. A partially humanized chimeric LO1-Fab-Cys localized similarly to the parent antibody in murine atheroma showing promise for future translation. PMID:26911995

  1. Lipid fluidity at different regions in LDL and HDL of {beta}-thalassemia/Hb E patients

    SciTech Connect

    Morales, Noppawan Phumala . E-mail: scnpm@mahidol.ac.th; Charlermchoung, Chalermkhwan; Luechapudiporn, Rataya; Yamanont, Paveena; Fucharoen, Suthat; Chantharaksri, Udom

    2006-11-24

    Atherosclerosis-related vascular complications in {beta}-thalassemia/hemoglobin E ({beta}-thal/Hb E) patients may result from iron induced oxidation of lipoproteins. To identify the specific site of oxidative damage, changes in lipid fluidity at different regions in LDL and HDL particle were investigated using two fluorescence probes and two ESR spin probes. The magnitude of increased lipid fluidity in thalassemic lipoproteins was dependent on the location of the probes. In hydrophobic region, the rotational correlation times for 16-doxyl stearic acid and DPH anisotropy were markedly changed in LDL and HDL of the patients. In the surface region, there was only a slight change in the order parameter (S) for 5-doxyl stearic acid and TMA-DPH anisotropy. Lipid fluidity at the core of LDL and HDL showed good correlation with oxidative stress markers, the ratio of CL/CO, and the level of {alpha}-tocopherol, suggesting that hydrophobic region of thalassemic lipoprotein was a target site for oxidative damage.

  2. Rapamycin down-regulates LDL-receptor expression independently of SREBP-2

    SciTech Connect

    Sharpe, Laura J.; Brown, Andrew J.

    2008-09-05

    As a key regulator of cholesterol homeostasis, sterol-regulatory element binding protein-2 (SREBP-2) up-regulates expression of genes involved in cholesterol synthesis (e.g., 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) Reductase) and uptake (the low density lipoprotein (LDL)-receptor). Previously, we showed that Akt, a critical kinase in cell growth and proliferation, contributes to SREBP-2 activation. However, the specific Akt target involved is unknown. A potential candidate is the mammalian target of rapamycin, mTOR. Rapamycin can cause hyperlipidaemia clinically, and we hypothesised that this may be mediated via an effect of mTOR on SREBP-2. Herein, we found that SREBP-2 activation and HMG-CoA Reductase gene expression were unaffected by rapamycin treatment. However, LDL-receptor gene expression was decreased by rapamycin, suggesting that this may contribute to the hyperlipidaemia observed in rapamycin-treated patients. Rapamycin did not affect mRNA stability, so the decrease in LDL-receptor gene expression is likely to be occurring at the transcriptional level, although independently of SREBP-2.

  3. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss.

    PubMed

    Kuo, Kung-Kai; Wu, Bin-Nan; Liu, Chung-Pin; Yang, Tzu-Yang; Kao, Li-Pin; Wu, Jiunn-Ren; Lai, Wen-Ter; Chen, Ing-Jun

    2015-11-01

    The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol, and LDL; increased HDL/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1-14 or 8-14 weeks decreased HFD-induced liver and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10(-7)∼10(-5) M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3',5'-cyclic monophosphate (cGMP) antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL and restored oxidized LDL-induced PKA expresion. Unlike simvastatin, KMUP-1 could not inhibit (14)C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight.

  4. Xanthine-based KMUP-1 improves HDL via PPARγ/SR-B1, LDL via LDLRs, and HSL via PKA/PKG for hepatic fat loss[S

    PubMed Central

    Kuo, Kung-Kai; Wu, Bin-Nan; Liu, Chung-Pin; Yang, Tzu-Yang; Kao, Li-Pin; Wu, Jiunn-Ren; Lai, Wen-Ter; Chen, Ing-Jun

    2015-01-01

    The phosphodiesterase inhibitor (PDEI)/eNOS enhancer KMUP-1, targeting G-protein coupled receptors (GPCRs), improves dyslipidemia. We compared its lipid-lowering effects with simvastatin and explored hormone-sensitive lipase (HSL) translocation in hepatic fat loss. KMUP-1 HCl (1, 2.5, and 5 mg/kg/day) and simvastatin (5 mg/kg/day) were administered in C57BL/6J male mice fed a high-fat diet (HFD) by gavage for 8 weeks. KMUP-1 inhibited HFD-induced plasma/liver TG, total cholesterol, and LDL; increased HDL/3-hydroxy-3-methylglutaryl-CoA reductase (HMGR)/Rho kinase II (ROCK II)/PPARγ/ABCA1; and decreased liver and body weight. KMUP-1 HCl in drinking water (2.5 mg/200 ml tap water) for 1–14 or 8–14 weeks decreased HFD-induced liver and body weight and scavenger receptor class B type I expression and increased protein kinase A (PKA)/PKG/LDLRs/HSL expression and immunoreactivity. In HepG2 cells incubated with serum or exogenous mevalonate, KMUP-1 (10−7∼10−5 M) reversed HMGR expression by feedback regulation, colocalized expression of ABCA1/apolipoprotein A-I/LXRα/PPARγ, and reduced exogenous geranylgeranyl pyrophosphate/farnesyl pyrophosphate (FPP)-induced RhoA/ROCK II expression. A guanosine 3′,5′-cyclic monophosphate (cGMP) antagonist reversed KMUP-1-induced ROCK II reduction, indicating cGMP/eNOS involvement. KMUP-1 inceased PKG and LDLRs surrounded by LDL and restored oxidized LDL-induced PKA expresion. Unlike simvastatin, KMUP-1 could not inhibit 14C mevalonate formation. KMUP-1 could, but simvastatin could not, decrease ROCK II expression by exogenous FPP/CGPP. KMUP-1 improves HDL via PPARγ/LXRα/ABCA1/Apo-I expression and increases LDLRs/PKA/PKG/HSL expression and immunoreactivity, leading to TG hydrolysis to lower hepatic fat and body weight. PMID:26351364

  5. Longitudinal Study of Low Serum LDL and Depressive Symptom Onset in Postmenopause

    PubMed Central

    Persons, Jane E.; Robinson, Jennifer G.; Coryell, William H.; Payne, Martha E.; Fiedorowicz, Jess G.

    2016-01-01

    Objective The aim of this study was to characterize the relationship between serum low-density lipoprotein cholesterol (LDL-c) and subsequent depressive symptoms onset in postmenopausal women. We secondarily assessed serum high-density lipoprotein (HDL-c), total cholesterol, and triglycerides. Methods This population-based prospective cohort study utilizes data from 24,216 50-79 year old participants of the Women’s Health Initiative, which originally ran from 1993-2005 and has since incorporated two extension studies, with the most recent culminating in 2015. Fasting lipids were measured for all participants at baseline, and for a subset through six years of follow-up. Depressive symptoms were characterized using the Burnam eight-item scale for depressive disorders (Center for Epidemiologic Studies-Depression/Diagnostic Interview Schedule short form) at baseline and over follow-up, using a cutpoint of 0.06 to indicate presence of depressive symptoms. Results The lowest quintile of LDL-c was associated with an increased risk of subsequent depressive symptoms (HR=1.25, CI 1.05-1.49, p=0.01) and follow-up analyses demonstrated that the elevated risk appeared to be confined to the lowest decile (LDL-c <100 mg/dL). Further, this elevated risk was moderated by lipid-lowering drug treatment. Elevated risk was demonstrated among those who reported no lipid-lowering medication use (HR=1.23, CI 1.03-1.47, p=0.02), but not among those reporting use (HR=0.65, CI 0.18-2.29, p=0.50). Conclusion Among postmenopausal women, untreated serum LDL-c below 100 mg/dL was associated with an increased risk of developing depressive symptoms. No excess risk was observed in those attaining LDL-c <100 mg/dl with lipid-lowering therapy. These findings have important implications for risk assessment, treatment considerations, and mechanistic insight. PMID:26930520

  6. Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling

    PubMed Central

    Chadipiralla, Kiranmai; Mendez, Armando J.; Jaimes, Edgar A.; Silverstein, Roy L.; Webster, Keith; Raij, Leopoldo

    2013-01-01

    Cigarette smoking is a major risk factor for atherosclerosis and cardiovascular disease. CD36 mediates oxidized LDL (oxLDL) uptake and contributes to macrophage foam cell formation. We investigated a role for the CD36 pathway in nicotine-induced activation of macrophages and foam cell formation in vitro and in vivo. Nicotine in the same plasma concentration range found in smokers increased the CD36+/CD14+ cell population in human peripheral blood mononuclear cells, increased CD36 expression of human THP1 macrophages, and increased macrophage production of reactive oxygen species, PKCδ phosphorylation, and peroxisome proliferator-activated receptor-γ (PPARγ) expression. Nicotine-induced CD36 expression was suppressed by antioxidants and by specific PKCδ and PPARγ inhibitors, implicating mechanistic roles for these intermediates. Nicotine synergized with oxLDL to increase macrophage expression of CD36 and cytokines TNF-α, monocyte chemoattractant protein-1, IL-6, and CXCL9, all of which were prevented by CD36 small interfering (si)RNA. Incubation with oxLDL (50 μg/ml) for 72 h resulted in lipid deposition in macrophages and foam cell formation. Preincubation with nicotine further increased oxLDL-induced lipid accumulation and foam cell formation, which was also prevented by CD36 siRNA. Treatment of apoE−/− mice with nicotine markedly exacerbated inflammatory monocyte levels and atherosclerotic plaque accumulation, effects that were not seen in CD36−/− apoE−/− mice. Our results show that physiological levels of nicotine increase CD36 expression in macrophages, a pathway that may account at least in part for the known proinflammatory and proatherogenic properties of nicotine. These results identify such enhanced CD36 expression as a novel nicotine-mediated pathway that may constitute an independent risk factor for atherosclerosis in smokers. The results also suggest that exacerbated atherogenesis by this pathway may be an adverse side effect of

  7. Novel phage group infecting Lactobacillus delbrueckii subsp. lactis, as revealed by genomic and proteomic analysis of bacteriophage Ldl1.

    PubMed

    Casey, Eoghan; Mahony, Jennifer; Neve, Horst; Noben, Jean-Paul; Dal Bello, Fabio; van Sinderen, Douwe

    2015-02-01

    Ldl1 is a virulent phage infecting the dairy starter Lactobacillus delbrueckii subsp. lactis LdlS. Electron microscopy analysis revealed that this phage exhibits a large head and a long tail and bears little resemblance to other characterized phages infecting Lactobacillus delbrueckii. In vitro propagation of this phage revealed a latent period of 30 to 40 min and a burst size of 59.9 +/- 1.9 phage particles. Comparative genomic and proteomic analyses showed remarkable similarity between the genome of Ldl1 and that of Lactobacillus plantarum phage ATCC 8014-B2. The genomic and proteomic characteristics of Ldl1 demonstrate that this phage does not belong to any of the four previously recognized L. delbrueckii phage groups, necessitating the creation of a new group, called group e, thus adding to the knowledge on the diversity of phages targeting strains of this industrially important lactic acid bacterial species.

  8. Role of lysophosphatidylcholine in the inhibition of endothelial cell motility by oxidized low density lipoprotein.

    PubMed Central

    Murugesan, G; Fox, P L

    1996-01-01

    Endothelial cell (EC) movement is required for the development and repair of blood vessels. We have previously shown that LDL oxidized by transition metals almost completely suppressed the wound-healing migratory response of vascular EC in vitro. We now report that lysophosphatidylcholine (lysoPC), a lipid component of oxidized LDL, has an important role in the antimigratory activity of the lipoprotein. Purified 1-palmitoyl lysoPC inhibited movement with a half-maximal activity at 12-15 micrometers, and near complete inhibition at 20 micrometers; the inhibitory concentration of lysoPC was consistent with its abundance in oxidized LDL. The inhibition was not due to cytotoxicity since protein synthesis was unaffected and since EC movement was restored after removal of lysoPC. Lysophospholipid activity was dependent on lipid structure. LysoPC's containing 1-position C16 or C18 saturated fatty acids were antimigratory, but those containing C < or = 14 saturated fatty acids or polyunsaturated fatty acids were not. The activity of 1-palmitoyl lysolipids with various head groups was examined. Lysophosphatidylinositol was more antimigratory than lysophosphatidylglycerol and lysophosphatidylcholine, which were more potent than lysophosphatidylserine and lysophosphatidylethanolamine. Monoglyceride was inactive while lysophosphatidate had promigratory activity. These results are consistent with head group size rather than charge as a critical determinant of activity. To show that lysophospholipids within an intact lipoprotein were active, LDL was treated with bee venom phospholipase A2 (PLA2). The modified lipoprotein inhibited EC movement to the same extent as iron-oxidized LDL and antimigratory activity correlated with the amount of lysoPC formed. To determine antimigratory activity of lysoPC present in oxidized LDL, lipid extracts from oxidized LDL were fractionated by normal phase HPLC. The fraction comigrating with lysoPC had nearly the same activity as the total extract

  9. Dysregulation of cystathionine γ-lyase (CSE)/hydrogen sulfide pathway contributes to ox-LDL-induced inflammation in macrophage.

    PubMed

    Wang, Xian-Hui; Wang, Fen; You, Shou-Jiang; Cao, Yong-Jun; Cao, Li-Dan; Han, Qiao; Liu, Chun-Feng; Hu, Li-Fang

    2013-11-01

    Hydrogen sulfide (H2S), mainly produced by cystathionine γ-lyase (CSE) in vascular system, emerges as a novel gasotransmitter exerting anti-inflammatory and anti-atherosclerotic effects. Alterations of CSE/H2S pathway may thus be involved in atherosclerosis pathogenesis. However, the underlying mechanisms are poorly understood. The present study showed that the levels of CSE mRNA and protein expression, as well as H2S production were decreased in ox-LDL-treated macrophage. CSE overexpression reduced the ox-LDL-stimulated tumor necrosis factor-α (TNF-α) generation in Raw264.7 and primary macrophage while CSE knockdown enhanced it. Exogenous supplementation of H2S with NaHS and Na2S also decreased the production of TNF-α and intercellular adhesion molecule-1 (ICAM-1) in ox-LDL-stimulated macrophage, and alleviated the adhesion of macrophage to endothelial monolayer. Cysteine, a CSE preferential substrate for H2S biosynthesis, produced similar effects on the pro-inflammatory cytokine generation, which were reversed by CSE inhibitors PAG and BCA, respectively. Moreover, NaHS and Na2S attenuated the phosphorylation and degradation of IκBα and p65 nuclear translocation, as well as JNK activation caused by ox-LDL. The JNK inhibitor suppressed the NF-κB transcription activity in ox-LDL-treated cells. Furthermore, inhibitors of NF-κB (PDTC), ERK (U0126 and PD98059) and JNK (SP600125) partially blocked the suppression by ox-LDL on the CSE mRNA levels. Taken together, the findings demonstrate that ox-LDL may down-regulate the CSE/H2S pathway, which plays an anti-inflammatory role in ox-LDL-stimulated macrophage by suppressing JNK/NF-κB signaling. The study reveals new therapeutic strategies for atherosclerosis, based on modulating CSE/H2S pathway.

  10. Atherosclerosis development in SLE patients is not determined by monocytes ability to bind/endocytose Ox-LDL.

    PubMed

    Yassin, Lina M; Londoño, Julián; Montoya, Guillermo; De Sanctis, Juan B; Rojas, Mauricio; Ramírez, Luis A; García, Luis F; Vásquez, Gloria

    2011-05-01

    Patients with systemic lupus erythematosus (SLE) have a high risk of developing cardiovascular disease; however, the mechanisms involved in the early onset of atherosclerosis in these patients are not clear. Scavenger receptors, CD36 and CD163 are expressed by mononuclear phagocytes and participate in the binding and uptake of oxidized low-density lipoproteins (Ox-LDL), contributing to foam-cells formation and atherosclerosis development. The aim of the present study was to evaluate CD36(+) and CD163(+) expression and Ox-LDL removal by monocytes from SLE and atherosclerotic patients, compared to similar age-range healthy controls. Healthy controls, SLE, and atherosclerotic patients were evaluated for carotid intima media thickness (CIMT), lipid profile, and native LDL (N-LDL) and Ox-LDL binding/endocytosis. SLE patients presented decreased high-density lipoproteins (HDL) and increased Triglyceride levels, and half of the SLE patients had increased CIMT, compared to their healthy controls (HC(SLE)). The number of CD14(+)CD163(+) cells was increased in atherosclerosis healthy controls (HC(Atheros)) compared to HC(SLE), but there were no differences between SLE or atherosclerotic patients and their respective healthy controls. Clearance assays revealed a similar capacity to bind/endocytose Ox-LDL by monocytes from SLE patients and HC(SLE), and an increased binding and endocytosis of Ox-LDL by monocytes from atherosclerotic patients, compared to HC(Atheros). The decreased CD36 and CD163 expression observed in atherosclerotic and SLE patients, respectively, suggest that these inflammatory conditions modulate these receptors differentially. The increased CIMT observed in SLE patients cannot be explained by Ox-LDL binding/endocytosis, which was comparable to their controls.

  11. Localization of genes for V+LDL plasma cholesterol levels on two diets in the opossum Monodelphis domestica[S

    PubMed Central

    Kammerer, Candace M.; Rainwater, David L.; Gouin, Nicolas; Jasti, Madhuri; Douglas, Kory C.; Dressen, Amy S.; Ganta, Prasanth; VandeBerg, John L.; Samollow, Paul B.

    2010-01-01

    Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 × 10−9). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 × 10−14) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet. PMID:20650928

  12. Localization of genes for V+LDL plasma cholesterol levels on two diets in the opossum Monodelphis domestica.

    PubMed

    Kammerer, Candace M; Rainwater, David L; Gouin, Nicolas; Jasti, Madhuri; Douglas, Kory C; Dressen, Amy S; Ganta, Prasanth; Vandeberg, John L; Samollow, Paul B

    2010-10-01

    Plasma cholesterol levels among individuals vary considerably in response to diet. However, the genes that influence this response are largely unknown. Non-HDL (V+LDL) cholesterol levels vary dramatically among gray, short-tailed opossums fed an atherogenic diet, and we previously reported that two quantitative trait loci (QTLs) influenced V+LDL cholesterol on two diets. We used hypothesis-free, genome-wide linkage analyses on data from 325 pedigreed opossums and located one QTL for V+LDL cholesterol on the basal diet on opossum chromosome 1q [logarithm of the odds (LOD) = 3.11, genomic P = 0.019] and another QTL for V+LDL on the atherogenic diet (i.e., high levels of cholesterol and fat) on chromosome 8 (LOD = 9.88, genomic P = 5 x 10(-9)). We then employed a novel strategy involving combined analyses of genomic resources, expression analysis, sequencing, and genotyping to identify candidate genes for the chromosome 8 QTL. A polymorphism in ABCB4 was strongly associated (P = 9 x 10(-14)) with the plasma V+LDL cholesterol concentrations on the high-cholesterol, high-fat diet. The results of this study indicate that genetic variation in ABCB4, or closely linked genes, is responsible for the dramatic differences among opossums in their V+LDL cholesterol response to an atherogenic diet.

  13. Changes in lipoprotein(a), oxidized phospholipids, and LDL subclasses with a low-fat high-carbohydrate diet

    PubMed Central

    Faghihnia, Nastaran; Tsimikas, Sotirios; Miller, Elizabeth R.; Witztum, Joseph L.; Krauss, Ronald M.

    2010-01-01

    Low-fat diets have been shown to increase plasma concentrations of lipoprotein(a) [Lp(a)], a preferential lipoprotein carrier of oxidized phospholipids (OxPLs) in plasma, as well as small dense LDL particles. We sought to determine whether increases in plasma Lp(a) induced by a low-fat high-carbohydrate (LFHC) diet are related to changes in OxPL and LDL subclasses. We studied 63 healthy subjects after 4 weeks of consuming, in random order, a high-fat low-carbohydrate (HFLC) diet and a LFHC diet. Plasma concentrations of Lp(a) (P < 0.01), OxPL/apolipoprotein (apo)B (P < 0.005), and OxPL-apo(a) (P < 0.05) were significantly higher on the LFHC diet compared with the HFLC diet whereas LDL peak particle size was significantly smaller (P < 0.0001). Diet-induced changes in Lp(a) were strongly correlated with changes in OxPL/apoB (P < 0.0001). The increases in plasma Lp(a) levels after the LFHC diet were also correlated with decreases in medium LDL particles (P < 0.01) and increases in very small LDL particles (P < 0.05). These results demonstrate that induction of increased levels of Lp(a) by an LFHC diet is associated with increases in OxPLs and with changes in LDL subclass distribution that may reflect altered metabolism of Lp(a) particles. PMID:20713651

  14. Image-based computational simulation of sub-endothelial LDL accumulation in a human right coronary artery.

    PubMed

    Nouri, Mohammad; Jalali, Farhang; Karimi, Gholamreza; Zarrabi, Khalil

    2015-07-01

    Accumulation of low density lipoproteins (LDL) in the vessel wall is suggested as the initiator of atherosclerosis and coronary stenosis. This process is associated with the performance of endothelium layer that regulates entering of macromolecules to the vessel wall. Therefore, the present study aims to investigate sub-endothelial accumulation of LDL molecules in a coronary tree and predict atherosclerosis prone sites. Non-Newtonian blood flow is simulated for normal and hypertensive conditions through the lumen of a right coronary artery reconstructed from computed tomography (CT) images. A three-pore model is implemented as the endothelium boundary condition and hence, plasma flow and LDL transport are simulated within the arterial wall. Based on the pore model, endothelium pathways divide into normal junctions, vesicles and leaky junctions. Most of LDL molecules pass through the leaky junctions that arise at locations with low wall shear stress (WSS). Results indicate that increase in the number of leaky junctions at branch points with low WSS can lead to both elevated levels of sub-endothelial LDL accumulation and atherosclerosis risk. Findings reveal that at the branch points with disturbed flow, sub-endothelial concentration of LDL for the hypertensive condition is higher than the normal condition, however for the rest of regions with uniform geometry and unidirectional flow, this is reversed. Comparisons of non-Newtonian and Newtonian flows show mean increases of 34% and 13% in the sub-endothelial concentrations of Newtonian flows during the normal and hypertensive conditions, respectively.

  15. Protective effect of high density lipoprotein associated paraoxonase. Inhibition of the biological activity of minimally oxidized low density lipoprotein.

    PubMed Central

    Watson, A D; Berliner, J A; Hama, S Y; La Du, B N; Faull, K F; Fogelman, A M; Navab, M

    1995-01-01

    Our group has previously demonstrated that oxidized phospholipids in mildly oxidized LDL (MM-LDL) produced by oxidation with lipoxygenase, iron, or cocultures of artery wall cells increase monocyte-endothelial interactions and this sequence of events is blocked by HDL. To obtain further insight into the mechanism by which HDL abolishes the activity of MM-LDL we investigated the effect of the HDL-associated ester hydrolase paraoxonase (PON). Treatment of MM-LDL with purified PON significantly reduced the ability of MM-LDL to induce monocyte-endothelial interactions. Inactivation of PON by pretreating HDL with heat or EDTA reduced the ability of HDL to inhibit LDL modification. HPLC analysis of phospholipids isolated from MM-LDL before and after treatment with purified PON showed that the 270 nm absorbance of phospholipids was decreased, while no effect was observed on 235 nm absorbance. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (Ox-PAPC) and specific fractions of Ox-PAPC isolated by HPLC induced the same monocyte-endothelial interactions as did MM-LDL. Biologically active and inactive HPLC fractions of Ox-PAPC were compared by fast atom bombardment-mass spectrometry which revealed that active fractions possessed ions with a mass to charge [correction of change] ratio greater than native PAPC by multiples of 16 D suggesting the addition of 3 and 4 oxygen atoms to PAPC. Comparison of Ox-PAPC by fast atom bombardment-mass spectrometry before and after PON treatment showed that PON destroyed these multi-oxygenated molecules found in biologically active fractions of Ox-PAPC. These results suggest that PON in HDL may protect against the induction of inflammatory responses in artery wall cells by destroying biologically active lipids in mildly oxidized LDL. Images PMID:8675659

  16. QTAIM charge-charge flux-dipole flux interpretation of electronegativity and potential models of the fluorochloromethane mean dipole moment derivatives.

    PubMed

    Silva, Arnaldo F; da Silva, João V; Haiduke, R L A; Bruns, Roy E

    2011-11-17

    Infrared fundamental vibrational intensities and quantum theory atoms in molecules (QTAIM) charge-charge flux-dipole flux (CCFDF) contributions to the polar tensors of the fluorochloromethanes have been calculated at the QCISD/cc-pVTZ level. A root-mean-square error of 20.0 km mol(-1) has been found compared to an experimental error estimate of 14.4 and 21.1 km mol(-1) for MP2/6-311++G(3d,3p) results. The errors in the QCISD polar tensor elements and mean dipole moment derivatives are 0.059 e when compared with the experimental values. Both theoretical levels provide results showing that the dynamical charge and dipole fluxes provide significant contributions to the mean dipole moment derivatives and tend to be of opposite signs canceling one another. Although the experimental mean dipole moment derivative values suggest that all the fluorochloromethane molecules have electronic structures consistent with a simple electronegativity model with transferable atomic charges for their terminal atoms, the QTAIM/CCFDF models confirm this only for the fluoromethanes. Whereas the fluorine atom does not suffer a saturation effect in its capacity to drain electronic charge from carbon atoms that are attached to other fluorine and chlorine atoms, the zero flux electronic charge of the chlorine atom depends on the number and kind of the other substituent atoms. Both the QTAIM carbon charges (r = 0.990) and mean dipole moment derivatives (r = 0.996) are found to obey Siegbahn's potential model for carbon 1s electron ionization energies at the QCISD/cc-pVTZ level. The latter is a consequence of the carbon mean derivatives obeying the electronegativity model and not necessarily to their similarities with atomic charges. Atomic dipole contributions to the neighboring atom electrostatic potentials of the fluorochloromethanes are found to be of comparable size to the atomic charge contributions and increase the accuracy of Siegbahn's model for the QTAIM charge model results

  17. Oxidized Low-Density Lipoprotein-β2-Glycoprotein I Complex But Not Free Oxidized LDL Is Associated With the Presence and Severity of Coronary Artery Disease.

    PubMed

    Bliden, Kevin P; Chaudhary, Rahul; Lopez, Luis R; Damrongwatanasuk, Rongras; Guyer, Kirk; Gesheff, Martin G; Franzese, Christopher J; Kaza, Himabindu; Tantry, Udaya S; Gurbel, Paul A

    2016-09-01

    Oxidized low-density lipoprotein (oxLDL) and β2-glycoprotein I (β2GPI) have been identified in human atherosclerotic lesions and when complexed have been implicated as a pro-atherothrombotic antigen. We examined the association of free oxLDL and oxLDL-β2GPI complex in patients with coronary artery disease who underwent elective cardiac catheterization. Serum was collected from patients with suspected coronary artery disease immediately before elective cardiac catheterization who were either treated (n = 385) or not treated (n = 150) with statins and from healthy volunteers (n = 134). OxLDL and oxLDL-β2GPI complex levels were determined by enzyme-linked immunosorbent assay. Disease severity was defined angiographically as none-minimal (<20%), moderate (20% to 75%), and severe (>75%) luminal diameter obstruction of any major coronary vessel. Both oxLDL and oxLDL-β2GPI complex were lower in patients on statins (p <0.001). In statin-naive patients, oxLDL-β2GPI complex, but not free oxLDL, was associated with severe coronary artery disease (p = 0.036). However, no association was observed in patients on statins. LDL4 and triglycerides increased with oxLDL-β2GPI complex quartiles (p = 0.001). OxLDL-β2GPI complex (>0.32 U/ml) was predictive of severe atherosclerosis by receiver-operating characteristic curve analysis in statin-naive patients (area under the curve 0.66, p = 0.002). In conclusion, oxLDL-β2GPI appears more predictive of coronary artery disease severity than oxLDL alone in statin-naive patients.

  18. Serum Oxidized LDL Decreases in Response to Statin Therapy and Relates Independently to Reductions in Coronary Plaque in Patients with HIV

    PubMed Central

    NOU, Eric; LU, Michael T.; LOOBY, Sara E.; FITCH, Kathleen V.; KIM, Elli A.; LEE, Hang; HOFFMANN, Udo; GRINSPOON, Steven K.; LO, Janet

    2016-01-01

    Objective Circulating oxidized LDL (oxLDL) levels are elevated in HIV-infected patients and have been associated with subclinical atherosclerosis. Statins have been shown to reduce plaque on coronary computed tomography angiography (cCTA) in HIV-infected individuals. Thus, we investigated the effect of statins on serum oxLDL levels and the relationship between changes in oxLDL and coronary atherosclerosis on cCTA in patients with HIV. Design We previously conducted a 12-month randomized, placebo-controlled trial with atorvastatin in forty HIV-infected subjects on stable anti-retroviral therapy with subclinical coronary atherosclerosis and LDL-cholesterol < 130 mg/dL. Methods In the current analysis, subjects underwent cCTA and measurements of serum oxLDL, sCD14, sCD163, lipoprotein phospholipase A2, and fasting lipids including direct LDL at baseline and end of the study. Results Nineteen subjects were randomized to atorvastatin and twenty-one subjects to placebo. Serum oxLDL decreased −22.7% [95% CI −28.7 to −16.7] in the atorvastatin group and increased 7.5% [95% CI −3.3 to 18.4] in the placebo group (p < 0.0001). Change in oxLDL significantly correlated with changes in non-calcified plaque volume, total plaque volume, positively remodeled plaque, and low attenuation plaque. The association between changes in oxLDL and non-calcified plaque volume was independent of the baseline 10-year Framingham risk, direct LDL, CD4 count, and viral load. Conclusions Statins lower oxLDL levels in HIV-infected patients, and reductions in oxLDL are related to improvements in coronary atherosclerosis, independent of traditional cardiovascular risk factors. Reductions in oxLDL may be one mechanism through which statins exert beneficial effects on reducing atherosclerosis in HIV-infected individuals. PMID:26558731

  19. Emergent biomarkers of residual cardiovascular risk in patients with low HDL-c and/or high triglycerides and average LDL-c concentrations: focus on HDL subpopulations, Oxidized LDL, adiponectin, and uric acid.

    PubMed

    Mascarenhas-Melo, Filipa; Palavra, Filipe; Marado, Daniela; Sereno, José; Teixeira-Lemos, Edite; Freitas, Isabel; Isabel-Mendonça, Maria; Pinto, Rui; Teixeira, Frederico; Reis, Flávio

    2013-01-01

    This study intended to determine the impact of HDL-c and/or TGs levels on patients with average LDL-c concentration, focusing on lipidic, oxidative, inflammatory, and angiogenic profiles. Patients with cardiovascular risk factors (n = 169) were divided into 4 subgroups, combining normal and low HDL-c with normal and high TGs patients. The following data was analyzed: BP, BMI, waist circumference and serum glucose, Total-c, TGs, LDL-c, oxidized-LDL, total HDL-c and HDL subpopulations, paraoxonase-1 (PON1) activity, hsCRP, uric acid, TNF- α , adiponectin, VEGF, and iCAM1. The two populations with increased TGs levels, regardless of the normal or low HDL-c, presented obesity and higher waist circumference, Total-c, LDL-c, Ox-LDL, and uric acid. Adiponectin concentration was significantly lower and VEGF was higher in the population with cumulative low values of HDL-c and high values of TGs, while HDL quality was reduced in the populations with impaired values of HDL-c and/or TGs, viewed by reduced large and increased small HDL subfractions. In conclusion, in a population with cardiovascular risk factors, low HDL-c and/or high TGs concentrations seem to be associated with a poor cardiometabolic profile, despite average LDL-c levels. This condition, often called residual risk, is better evidenced by using both traditional and nontraditional CV biomarkers, including large and small HDL subfractions, Ox-LDL, adiponectin, VEGF, and uric acid.

  20. Endothelial cytoprotection from oxidized LDL by some crude Melanesian plant extracts is not related to their antioxidant capacity.

    PubMed

    Owen, Patrick L; Matainaho, Teatulohi; Sirois, Martin; Johns, Timothy

    2007-01-01

    Habitual consumption of some Melanesian medicinal and food plants may influence atherosclerosis development via their antioxidant capacity at the endothelial level. Areca nut (AN; Areca catechu), piper inflorescence (PBI; Piper betle), betel quid (BQ), guava buds (GB; Psidium guajava), the leaves (NL), juice (NJ), fruit (NF), and root (NR) of noni (Morinda citrifolia), the propagules of raw (MBR), and cooked (MBC) mangrove (Bruguiera gymnorrhiza) were evaluated for their ability to scavenge the 1,1-diphenyl-2-picryl-hydrazyle (DPPH) radical, to protect human low-density lipoprotein (LDL) from Cu2+-catalyzed oxidation and to protect cultured bovine aortal endothelial cells (BAEC) from oxidized LDL (oxLDL)-induced cytotoxicity. Polyphenol-rich extracts AN, PBI, and BQ were potent DPPH scavengers, having similar activity to quercetin and able to protect LDL from oxidation in a dose-dependent manner at concentrations higher than 10 microg/mL, but were pro-oxidants at lower concentrations. These extracts were cytotoxic to BAEC at concentrations above 10 microg/mL and were unable to prevent oxLDL endotheliopathy. GB and NR at 10 mug/mL displayed both the ability to delay LDL oxidation and prevent oxLDL cytotoxicity, although the latter lacked the ability to scavenge the DPPH radical. At higher concentrations, however, both were cytotoxic in themselves. The remaining noni extracts NF, NJ, NL, and both mangrove extracts MBC and MBR were unable to protect LDL from oxidation at all tested concentrations, but were effective cytoprotective agents at 50 microg/mL. All extracts were able to prevent an oxLDL-mediated increase in intracellular aldehyde generation but had little effect on extracellular peroxidation as measured by thiobarbituric acid reactive substances (TBARS). On the basis of this model system, we conclude that the antioxidant benefits of AN, PBI, and BQ may be offset by their enhancement of their cytotoxic effects of oxLDL toward BAEC, whereas GB and low

  1. MicroRNAs expression in ox-LDL treated HUVECs: MiR-365 modulates apoptosis and Bcl-2 expression

    SciTech Connect

    Qin, Bing; Xiao, Bo; Liang, Desheng; Xia, Jian; Li, Ye; Yang, Huan

    2011-06-24

    Highlights: {yields} We evaluated the role of miRNAs in ox-LDL induced apoptosis in ECs. {yields} We found 4 up-regulated and 11 down-regulated miRNAs in apoptotic ECs. {yields} Target genes of the dysregulated miRNAs regulate ECs apoptosis and atherosclerosis. {yields} MiR-365 promotes ECs apoptosis via suppressing Bcl-2 expression. {yields} MiR-365 inhibitor alleviates ECs apoptosis induced by ox-LDL. -- Abstract: Endothelial cells (ECs) apoptosis induced by oxidized low-density lipoprotein (ox-LDL) is thought to play a critical role in atherosclerosis. MicroRNAs (miRNAs) are a class of noncoding RNAs that posttranscriptionally regulate the expression of genes involved in diverse cell functions, including differentiation, growth, proliferation, and apoptosis. However, whether miRNAs are associated with ox-LDL induced apoptosis and their effect on ECs is still unknown. Therefore, this study evaluated potential miRNAs and their involvement in ECs apoptosis in response to ox-LDL stimulation. Microarray and qRT-PCR analysis performed on human umbilical vein endothelial cells (HUVECs) exposed to ox-LDL identified 15 differentially expressed (4 up- and 11 down-regulated) miRNAs. Web-based query tools were utilized to predict the target genes of the differentially expressed miRNAs, and the potential target genes were classified into different function categories with the gene ontology (GO) term and KEGG pathway annotation. In particular, bioinformatics analysis suggested that anti-apoptotic protein B-cell CLL/lymphoma 2 (Bcl-2) is a target gene of miR-365, an apoptomir up-regulated by ox-LDL stimulation in HUVECs. We further showed that transfection of miR-365 inhibitor partly restored Bcl-2 expression at both mRNA and protein levels, leading to a reduction of ox-LDL-mediated apoptosis in HUVECs. Taken together, our findings indicate that miRNAs participate in ox-LDL-mediated apoptosis in HUVECs. MiR-365 potentiates ox-LDL-induced ECs apoptosis by regulating the

  2. Chronic depletion of glutathione (GSH) and minimal modification of LDL in vivo: its prevention by glutathione mono ester (GME) therapy.

    PubMed

    Rajasekaran, Namakkal Soorappan; Sathyanarayanan, Srinivasan; Devaraj, Niranjali S; Devaraj, Halagowder

    2005-06-30

    A decline in reduced glutathione (GSH) level is associated with aging and free radical mediated diseases. The objective of this study was to determine whether the chronic depletion of extra cellular GSH causes oxidative damage to the circulating macromolecules such as lipoproteins. Decreased concentrations of plasma glutathione, vitamin E and ascorbic acid were recorded in the rats treated with buthionine sulfoximine (BSO), a selective GSH inhibitor. In LDL isolated from BSO-treated animals, the concentration of malondialdehyde (MDA) and conjugated dienes were significantly increased (P<0.01), whereas the levels of vitamin E were decreased (P<0.01). The analysis of total and LDL cholesterol revealed significant changes between the control and experimental groups. Of interest, altered concentrations of lyso-phosphatidyl choline (Lyso-PC) and phosphatidyl choline (PC) were recorded from the BSO mediated minimally modified LDL. A negative correlation between LDL-BDC/MDA and its antioxidant capacity was noted. Upon in vitro oxidation with CuSO(4), the electrophoretic behavior of purified LDL-apoprotein-B on agarose gel showed an increased mobility in BSO-treated rats, indicative of in vivo modification of LDL to become susceptible for in vitro oxidation. The increased mobility of LDL (after in vitro oxidation) isolated from the BSO-treated animals correlates with a decrease in its amino groups, as determined by the trinitrobenzene sulfonic acid (TNBS) reactants. However, the mobility of LDL molecule was not altered due to BSO treatment in vivo. Interestingly, the minimal modification on LDL does not lead to any vascular damage in the dorsal aorta of the rats injected with BSO. The administration of glutathione monoester (GME), at a dose of 5 mmol/kg body weight, twice a day, for 30 days, to animals treated with l-buthionine-SR-sulfoximine (BSO, 4 mmol/kg body weight, twice a day, for 30 days) normalized the antioxidant status and prevented the minimal modifications on

  3. Antioxidant action of eugenol compounds: role of metal ion in the inhibition of lipid peroxidation.

    PubMed

    Ito, Masae; Murakami, Keiko; Yoshino, Masataka

    2005-03-01

    Antioxidant action of eugenol compounds was analyzed in relation to the role of transition metal. Iron-mediated lipid peroxidation and autooxidation of Fe2+ ion were inhibited markedly by isoeugenol, and less effectively by eugenol. Copper-dependent oxidation of low density lipoprotein (LDL) was potently inhibited by eugenol and isoeugenol to the same extent: eugenol compounds showed protective effects by prolonging lag phase and by suppressing propagation rate in the absence and presence of alpha-tocopherol. Inhibition of LDL oxidation by eugenol compounds was closely related to activities reducing copper and scavenging a stable radical, 1,1'-diphenyl-2-picrylhydrazyl (DPPH). Antioxidant properties of eugenol compounds can be explained by forming complexes with reduced metals. Potent inhibitory effect of isoeugenol on lipid peroxidation may be related to the decreased formation of perferryl ion or the iron-oxygen chelate complex as the initiating factor of lipid peroxidation by keeping iron at a reduced state. Inhibition of LDL oxidation by eugenol compounds is due to the suppression of free radical cascade of lipid peroxidation in LDL by reducing copper ion.

  4. From chemistry to mechanics: bulk modulus evolution of Li-Si and Li-Sn alloys via the metallic electronegativity scale.

    PubMed

    Li, Keyan; Xie, Hui; Liu, Jun; Ma, Zengsheng; Zhou, Yichun; Xue, Dongfeng

    2013-10-28

    Toward engineering high performance anode alloys for Li-ion batteries, we proposed a useful method to quantitatively estimate the bulk modulus of binary alloys in terms of metallic electronegativity (EN), alloy composition and formula volume. On the basis of our proposed potential viewpoint, EN as a fundamental chemistry concept can be extended to be an important physical parameter to characterize the mechanical performance of Li-Si and Li-Sn alloys as anode materials for Li-ion batteries. The bulk modulus of binary alloys is linearly proportional to the combination of average metallic EN and atomic density of alloys. We calculated the bulk moduli of Li-Si and Li-Sn alloys with different Li concentrations, which can agree well with the reported data. The bulk modulus of Li-Si and Li-Sn alloys decreases with increasing Li concentration, leading to the elastic softening of the alloys, which is essentially caused by the decreased strength of constituent chemical bonds in alloys from the viewpoint of EN. This work provides a deep understanding of mechanical failure of Si and Sn anodes for Li-ion batteries, and permits the prediction of the composition dependent bulk modulus of various lithiated alloys on the basis of chemical formula, metallic EN and cell volume (or alloy density), with no structural details required.

  5. Bridging the gap between global models and full fluid models: a fast 1D semi-analytical fluid model for electronegative plasmas

    NASA Astrophysics Data System (ADS)

    Hurlbatt, A.; O'Connell, D.; Gans, T.

    2016-08-01

    Analytical and numerical models allow investigation of complicated discharge phenomena and the interplay that makes plasmas such a complex environment. Global models are quick to implement and can have almost negligible computation cost, but provide only bulk or spatially averaged values. Full fluid models take longer to develop, and can take days to solve, but provide accurate spatio-temporal profiles of the whole plasma. The work presented here details a different type of model, analytically similar to fluid models, but computationally closer to a global model, and able to give spatially resolved solutions for the challenging environment of electronegative plasmas. Included are non-isothermal electrons, gas heating, and coupled neutral dynamics. Solutions are reached in seconds to minutes, and spatial profiles are given for densities, fluxes, and temperatures. This allows the semi-analytical model to fill the gap that exists between global and full fluid models, extending the tools available to researchers. The semi-analytical model can perform broad parameter sweeps that are not practical with more computationally expensive models, as well as exposing non-trivial trends that global models cannot capture. Examples are given for a low pressure oxygen CCP. Excellent agreement is shown with a full fluid model, and comparisons are drawn with the corresponding global model.

  6. Towards a fully kinetic 3D electromagnetic particle-in-cell model of streamer formation and dynamics in high-pressure electronegative gases

    NASA Astrophysics Data System (ADS)

    Rose, D. V.; Welch, D. R.; Clark, R. E.; Thoma, C.; Zimmerman, W. R.; Bruner, N.; Rambo, P. K.; Atherton, B. W.

    2011-09-01

    Streamer and leader formation in high pressure devices is dynamic process involving a broad range of physical phenomena. These include elastic and inelastic particle collisions in the gas, radiation generation, transport and absorption, and electrode interactions. Accurate modeling of these physical processes is essential for a number of applications, including high-current, laser-triggered gas switches. Towards this end, we present a new 3D implicit particle-in-cell simulation model of gas breakdown leading to streamer formation in electronegative gases. The model uses a Monte Carlo treatment for all particle interactions and includes discrete photon generation, transport, and absorption for ultra-violet and soft x-ray radiation. Central to the realization of this fully kinetic particle treatment is an algorithm that manages the total particle count by species while preserving the local momentum distribution functions and conserving charge [D. R. Welch, T. C. Genoni, R. E. Clark, and D. V. Rose, J. Comput. Phys. 227, 143 (2007)]. The simulation model is fully electromagnetic, making it capable of following, for example, the evolution of a gas switch from the point of laser-induced localized breakdown of the gas between electrodes through the successive stages of streamer propagation, initial electrode current connection, and high-current conduction channel evolution, where self-magnetic field effects are likely to be important. We describe the model details and underlying assumptions used and present sample results from 3D simulations of streamer formation and propagation in SF6.

  7. Rogue waves in electronegative space plasmas: The link between the family of the KdV equations and the nonlinear Schrödinger equation

    NASA Astrophysics Data System (ADS)

    El-Tantawy, S. A.

    2016-05-01

    We examine the likelihood of the ion-acoustic rogue waves propagation in a non-Maxwellian electronegative plasma in the framework of the family of the Korteweg-de Vries (KdV) equations (KdV/modified KdV/Extended KdV equation). For this purpose, we use the reductive perturbation technique to carry out this study. It is known that the family of the KdV equations have solutions of distinct structures such as solitons, shocks, kinks, cnoidal waves, etc. However, the dynamics of the nonlinear rogue waves is governed by the nonlinear Schrödinger equation (NLSE). Thus, the family of the KdV equations is transformed to their corresponding NLSE developing a weakly nonlinear wave packets. We show the possible region for the existence of the rogue waves and define it precisely for typical parameters of space plasmas. We investigate numerically the effects of relevant physical parameters, namely, the negative ion relative concentration, the nonthermal parameter, and the mass ratio on the propagation of the rogue waves profile. The present study should be helpful in understanding the salient features of the nonlinear structures such as, ion-acoustic solitary waves, shock waves, and rogue waves in space and in laboratory plasma where two distinct groups of ions, i.e. positive and negative ions, and non-Maxwellian (nonthermal) electrons are present.

  8. Atorvastatin treatment and LDL cholesterol target attainment in patients at very high cardiovascular risk.

    PubMed

    Laufs, Ulrich; Karmann, Barbara; Pittrow, David

    2016-09-01

    The use of atorvastatin is rapidly increasing among statins since the introduction of generics. However, only limited data are available on its current use and the effectiveness outside of randomised trials. The aim of the study was to assess low-density lipoprotein (LDL-C) levels in ambulatory patients at very high cardiovascular risk on atorvastatin therapy in physician's offices. A total of 2625 high-risk patients on atorvastatin were included into this cross-sectional study by 539 office-based physicians between June and December 2014. 47.0 % of the patients had documented coronary heart disease (CHD), 25.1 % type 2 diabetes mellitus (DM), and 27.9 % CHD plus concomitant DM. The mean age was 66.1 ± 10.8 years, 62.1 % were male. Atorvastatin at the dose of 10, 20, 40 and 80 mg/day was administered in 15.6, 45.7, 33.9, and 4.8 % of the patients, respectively. The treatment duration was 92.6 ± 109.6 weeks. The mean atorvastatin dose at therapy start was 24.8 ± 15.2 mg/day and at time of documentation 27.9 ± 15.8 mg/day. Low-density lipoprotein cholesterol (LDL-C) <70 mg/dL was achieved by 10.5 % of the total cohort (7.5 % in DM, 9.3 % in CHD, and 15.2 % in CHD + DM). In contrast, according to physicians' subjective assessment, 62.7 % of patients (with small differences between groups) had reached their individual LDL-C target. In summary, higher doses of atorvastatin are not frequently used in clinical practice. The LDL-C target level <70 mg/dL as recommended by current guidelines is achieved only in a minority of atorvastatin treated patients at very high cardiovascular risk.

  9. Tiliroside and gnaphaliin inhibit human low density lipoprotein oxidation.

    PubMed

    Schinella, Guillermo R; Tournier, Horacio A; Máñez, Salvador; de Buschiazzo, Perla M; Del Carmen Recio, María; Ríos, José Luis

    2007-01-01

    Two flavonoids, gnaphaliin and tiliroside, isolated from Helichrysum italicum, were studied in vitro for their capacity to inhibit Cu(2+)-induced human low density lipoprotein (LDL) and diluted plasma oxidation. LDL oxidation was monitored by conjugated diene, thiobarbituric acid-reactive substances (TBARS) formation and electrophoretic mobility on agarose gel. Gnaphaliin and tiliroside increased the lag-phase for diene conjugate production in a dose-dependent manner. The reduction of TBARS production confirmed the antioxidant activity of gnaphaliin and tiliroside with 50% inhibitory concentration (IC(50)) values of 8.0+/-3.9 microM and 7.0+/-2.6 microM respectively. Furthermore, the flavonoids negated the Cu(2+)-induced increase in electrophoretic mobility of LDL. Antioxidant activity of gnaphaliin and tiliroside was significantly different when diluted plasma was oxidised by adding 1 mM CuSO(4). Although both flavonoids again reduced the TBARS production, tiliroside showed higher activity than gnaphaliin (IC(50)=10.6+/-2.5 microM vs. IC(50)>50 microM). In conclusion, tiliroside and gnaphaliin are antioxidants against in vitro Cu(2+)-induced LDL oxidation in the same order of magnitude compared to that of the reference drug, probucol.

  10. A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients1[S

    PubMed Central

    Cubedo, Judit; Padró, Teresa; García-Arguinzonis, Maisa; Vilahur, Gemma; Miñambres, Inka; Pou, Jose María; Ybarra, Juan; Badimon, Lina

    2015-01-01

    Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients. PMID:26168996

  11. LDL-apheresis depletes apoE-HDL and pre-β1-HDL in familial hypercholesterolemia: relevance to atheroprotection

    PubMed Central

    Orsoni, Alexina; Saheb, Samir; Levels, Johannes H. M.; Dallinga-Thie, Geesje; Atassi, Marielle; Bittar, Randa; Robillard, Paul; Bruckert, Eric; Kontush, Anatol; Carrié, Alain; Chapman, M. John

    2011-01-01

    Subnormal HDL-cholesterol (HDL-C) and apolipoprotein (apo)AI levels are characteristic of familial hypercholesterolemia (FH), reflecting perturbed intravascular metabolism with compositional anomalies in HDL particles, including apoE enrichment. Does LDL-apheresis, which reduces HDL-cholesterol, apoAI, and apoE by adsorption, induce selective changes in HDL subpopulations, with relevance to atheroprotection? Five HDL subpopulations were fractionated from pre- and post-LDL-apheresis plasmas of normotriglyceridemic FH subjects (n = 11) on regular LDL-apheresis (>2 years). Apheresis lowered both plasma apoE (−62%) and apoAI (−16%) levels, with preferential, genotype-independent reduction in apoE. The mass ratio of HDL2:HDL3 was lowered from ∼1:1 to 0.72:1 by apheresis, reflecting selective removal of HDL2 mass (80% of total HDL adsorbed). Pre-LDL-apheresis, HDL2 subpopulations were markedly enriched in apoE, consistent with ∼1 copy of apoE per 4 HDL particles. Large amounts (50-66%) of apoE-HDL were removed by apheresis, preferentially in the HDL2b subfraction (−50%); minor absolute amounts of apoE-HDL were removed from HDL3 subfractions. Furthermore, pre-β1-HDL particle levels were subnormal following removal (−53%) upon apheresis, suggesting that cellular cholesterol efflux may be defective in the immediate postapheresis period. In LDL-receptor (LDL-R) deficiency, LDL-apheresis may enhance flux through the reverse cholesterol transport pathway and equally attenuate potential biglycan-mediated deposition of apoE-HDL in the arterial matrix. PMID:21957200

  12. Proprotein convertase subtilisin/kexin type 9 inhibition: a new therapeutic mechanism for reducing cardiovascular disease risk.

    PubMed

    Bergeron, Nathalie; Phan, Binh An P; Ding, Yunchen; Fong, Aleyna; Krauss, Ronald M

    2015-10-27

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.

  13. AMP-activated protein kinase attenuates oxLDL uptake in macrophages through PP2A/NF-κB/LOX-1 pathway.

    PubMed

    Chen, Bo; Li, Jin; Zhu, Haibo

    2016-10-01

    The differentiation of macrophages into lipid-laden foam cells is a hallmark in early-stage atherosclerosis. The developmental role of adenosine monophosphate-activated protein kinase (AMPK) in a transformation of foam cells, especially in macrophage cholesterol uptake that remains undetermined. Here we demonstrate that AMPK activation in response to IMM-H007 or AICAR resulted in a decrease in macrophage cholesterol uptake and thus inhibited foam cell formation in macrophages mediated by oxidized low-density lipoprotein (oxLDL). This functional change was caused by a downregulation of mRNA and protein expression of LOX-1 but not other scavenger receptors, including scavenger receptor-A (SR-A), CD36 and scavenger receptor-BI (SR-BI). The expression of LOX-1 was regulated by AMPK activation induced decreased phosphorylation of nuclear transcription factor NF-κB, since siRNA interference or dominant negative AMPK overexpression significantly promotes Ser536 dephosphorylation of NF-κB p65 and thus increases LOX-1 expression. Moreover, pharmacological AMPK activation was shown to promote protein phosphatase 2A (PP2A) activity and the specific PP2A inhibitor, okadaic acid, could prevent the effects of IMM-H007 or AICAR on NF-κB and LOX-1. In vivo, pharmacological AMPK activation reduced the lesion size of atherosclerosis and the expression of LOX-1 in aortas in apolipoprotein E-deficient mice. Our current findings suggest a novel mechanism of LOX-1 regulation by AMPK to attenuate macrophage oxLDL uptake and atherosclerosis.

  14. Inhibition of leukocyte-type 12-lipoxygenase by guava tea leaves prevents development of atherosclerosis.

    PubMed

    Takahashi, Yoshitaka; Otsuki, Akemi; Mori, Yoshiko; Kawakami, Yuki; Ito, Hideyuki

    2015-11-01

    Oxidation of low-density lipoprotein (LDL) is one of the crucial steps for atherosclerosis development, and an essential role of leukocyte-type 12-lipoxygenase expressed in macrophages in this process has been demonstrated. The biochemical mechanism of the oxidation of circulating LDL by leukocyte-type 12-lipoxygenase in macrophages has been proposed. The major ingredients in guava tea leaves which inhibited the catalytic activity of leukocyte-type 12-lipoxygenase were quercetin and ethyl gallate. Administration of extracts from guava tea leaves to apoE-deficient mice significantly attenuated atherogenic lesions in the aorta and aortic sinus. We recently showed that Qing Shan Lu Shui inhibited the catalytic activity of leukocyte-type 12-lipoxygenase. The major components inhibiting the enzyme contained in Qing Shan Lu Shui were identified to be novel monoterpene glycosides. The anti-atherogenic effect of the tea leaves might be attributed to the inhibition of leukocyte-type 12-lipoxygenase by these components.