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Application of multianalyte microphysiometry to characterize macrophage metabolic responses to oxidized LDL and effects of an apoA-1 mimetic.
Kimmel DW, Dole WP, Cliffel DE
(2013) Biochem Biophys Res Commun 431: 181-5
MeSH Terms: Animals, Apolipoprotein A-I, Atherosclerosis, Biomimetic Materials, Cell Line, Glucose, Lactic Acid, Lipoproteins, LDL, Macrophages, Mice, Oxygen, Peptides, Potentiometry
Show Abstract · Added January 20, 2015
Although the interaction of macrophages with oxidized low density liopoprotein (oxLDL) is critical to the pathogenesis of atherosclerosis, relatively little is known about their metabolic response to oxLDL. Our development of the multianalyte microphysiometer (MAMP) allows for simultaneous measurement of extracellular metabolic substrates and products in real-time. Here, we use the MAMP to study changes in the metabolic rates of RAW-264.7 cells undergoing respiratory burst in response to oxLDL. These studies indicate that short duration exposure of macrophages to oxLDL results in time-dependent increases in glucose and oxygen consumption and in lactate production and extracellular acidification rate. Since apolipoprotein A-I (apoA-I) and apoA-I mimetics prevent experimental atherosclerosis, we hypothesized that the metabolic response of the macrophage during respiratory burst can be modulated by apoA-I mimetics. We tested this hypothesis by examining the effects of the apoA-I peptide mimetic, L-4F, alone and complexed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) on the macrophage metabolic response to oxLDL. L-4F and the DMPC/L-4F complexes attenuated the macrophage respiratory burst in response to oxLDL. The MAMP provides a novel approach for studying macrophage ligand-receptor interactions and cellular metabolism and our results provide new insights into the metabolic effects of oxLDL and mechanism of action of apoA-I mimetics.
Copyright © 2013 Elsevier Inc. All rights reserved.
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13 MeSH Terms
EphA2 activation promotes the endothelial cell inflammatory response: a potential role in atherosclerosis.
Funk SD, Yurdagul A, Albert P, Traylor JG, Jin L, Chen J, Orr AW
(2012) Arterioscler Thromb Vasc Biol 32: 686-95
MeSH Terms: Animals, Apolipoproteins E, Atherosclerosis, Cell Adhesion, Cells, Cultured, Coculture Techniques, Cytokines, Disease Models, Animal, Endothelial Cells, Gene Expression Regulation, Human Umbilical Vein Endothelial Cells, Humans, Inflammation, Inflammation Mediators, Lipoproteins, LDL, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes, Phenotype, RNA Interference, Receptor, EphA2, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transfection
Show Abstract · Added March 5, 2014
OBJECTIVE - Endothelial cell activation results in altered cell-cell interactions with adjacent endothelial cells and with infiltrating leukocytes. Eph receptors and their ephrin ligands regulate cell-cell interactions during tissue remodeling, and multiple proinflammatory mediators induce endothelial EphA receptor and ephrinA ligand expression. Therefore, we sought to elucidate the role of EphA receptors and ephrinA ligands in endothelial cell activation and atherosclerosis.
METHODS AND RESULTS - Quantitative reverse transcription-polymerase chain reaction screening for EphA/ephrinA expression in atherosclerosis-prone macrovascular endothelium identified EphA2, EphA4, and ephrinA1 as the dominant isoforms. Endothelial activation with oxidized low-density lipoprotein and proinflammatory cytokines induced EphA2 and ephrinA1 expression and sustained EphA2 activation, whereas EphA4 expression was unaffected. Atherosclerotic plaques from mice and humans showed enhanced EphA2 and ephrinA1 expression colocalizing in the endothelial cell layer. EphA2 activation with recombinant Fc-ephrinA1 induced proinflammatory gene expression (eg vascular cell adhesion molecule-1, E-selectin) and stimulated monocyte adhesion, whereas inhibiting EphA2 (small interfering RNA, pharmacological inhibitors) abrogated both ephrinA1-induced and oxidized low-density lipoprotein-induced vascular cell adhesion molecule-1 expression.
CONCLUSION - The current data suggest that enhanced EphA2 signaling during endothelial cell activation perpetuates proinflammatory gene expression. Coupled with EphA2 expression in mouse and human atherosclerotic plaques, these data implicate EphA2 as a novel proinflammatory mediator and potential regulator of atherosclerotic plaque development.
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27 MeSH Terms
High-fat meal effect on LDL, HDL, and VLDL particle size and number in the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN): an interventional study.
Wojczynski MK, Glasser SP, Oberman A, Kabagambe EK, Hopkins PN, Tsai MY, Straka RJ, Ordovas JM, Arnett DK
(2011) Lipids Health Dis 10: 181
MeSH Terms: Adult, Aged, Cardiovascular Diseases, Cholesterol, VLDL, Cohort Studies, Dietary Fats, Family Health, Female, Humans, Hypertriglyceridemia, Lipoproteins, HDL, Lipoproteins, IDL, Lipoproteins, LDL, Lipoproteins, VLDL, Magnetic Resonance Spectroscopy, Male, Middle Aged, Particle Size, Postprandial Period, Risk Factors, Sex Characteristics, Triglycerides, United States
Show Abstract · Added April 23, 2015
BACKGROUND - Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.
RESULTS - Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.
CONCLUSIONS - We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
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23 MeSH Terms
Dysfunctional HDL containing L159R ApoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice.
Sorci-Thomas MG, Zabalawi M, Bharadwaj MS, Wilhelm AJ, Owen JS, Asztalos BF, Bhat S, Thomas MJ
(2012) Biochim Biophys Acta 1821: 502-12
MeSH Terms: Animals, Aorta, Apolipoprotein A-I, Apolipoproteins, Apolipoproteins E, Atherosclerosis, Cells, Cultured, Cholesterol, Diet, Atherogenic, Female, Gene Expression, Humans, Hyperlipidemias, Lipoproteins, HDL, Lipoproteins, LDL, Male, Mice, Mice, Inbred C57BL, Mice, Inbred DBA, Mice, Transgenic, Mutation, Missense, Triglycerides
Show Abstract · Added January 20, 2015
The mutation L159R apoA-I or apoA-I(L159R) (FIN) is a single amino acid substitution within the sixth helical repeat of apoA-I. It is associated with a dominant negative phenotype, displaying hypoalphaproteinemia and an increased risk for atherosclerosis in humans. Mice lacking both mouse apoA-I and LDL receptor (LDL(-/-), apoA-I(-/-)) (double knockout or DKO) were crossed>9 generations with mice transgenic for human FIN to obtain L159R apoA-I, LDLr(-/-), ApoA-I(-/-) (FIN-DKO) mice. A similar cross was also performed with human wild-type (WT) apoA-I (WT-DKO). In addition, FIN-DKO and WT-DKO were crossed to obtain WT/FIN-DKO mice. To determine the effects of the apoA-I mutations on atherosclerosis, groups of each genotype were fed either chow or an atherogenic diet for 12weeks. Interestingly, the production of dysfunctional HDL-like particles occurred in DKO and FIN-DKO mice. These particles were distinct with respect to size, and their enrichment in apoE and cholesterol esters. Two-dimensional gel electrophoresis indicated that particles found in the plasma of FIN-DKO mice migrated as large α(3)-HDL. Atherosclerosis analysis showed that FIN-DKO mice developed the greatest extent of aortic cholesterol accumulation compared to all other genotypes, including DKO mice which lack any apoA-I. Taken together these data suggest that the presence of large apoE enriched HDL particles containing apoA-I L159R lack the normal cholesterol efflux promoting properties of HDL, rendering them dysfunctional and pro-atherogenic. In conclusion, large HDL-like particles containing apoE and apoA-I(L159R) contribute rather than protect against atherosclerosis, possibly through defective efflux properties and their potential for aggregation at their site of interaction in the aorta. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
Copyright © 2011 Elsevier B.V. All rights reserved.
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22 MeSH Terms
Lipoprotein lipase S447X variant associated with VLDL, LDL and HDL diameter clustering in the MetS.
Wood AC, Glasser S, Garvey WT, Kabagambe EK, Borecki IB, Tiwari HK, Tsai MY, Hopkins PN, Ordovas JM, Arnett DK
(2011) Lipids Health Dis 10: 143
MeSH Terms: Adult, Aged, Amino Acid Substitution, Cluster Analysis, Female, Gene Frequency, Genetic Association Studies, Genetic Predisposition to Disease, Humans, Insulin Resistance, Lipoprotein Lipase, Lipoproteins, HDL, Lipoproteins, LDL, Lipoproteins, VLDL, Male, Metabolic Syndrome, Middle Aged, Particle Size, Pedigree, Polymorphism, Genetic, Polymorphism, Single Nucleotide, United States
Show Abstract · Added April 23, 2015
BACKGROUND - Previous analysis clustered 1,238 individuals from the general population Genetics of Lipid Lowering Drugs Network (GOLDN) study by the size of their fasting very low-density, low-density and high-density lipoproteins (VLDL, LDL, HDL) using latent class analysis. From two of the eight identified groups (N = 251), ~75% of individuals met Adult Treatment Panel III criteria for the metabolic syndrome (MetS). Both showed small LDL diameter (mean = 19.9 nm); however, group 1 (N = 200) had medium VLDL diameter (mean = 53.1 nm) while group 2 had very large VLDL diameter (mean = 65.74 nm). Group 2 additionally showed significantly more insulin resistance (IR), and accompanying higher waist circumference and fasting glucose and triglycerides (all P < .01). Since lipoprotein lipase hydrolyzes triglyceride in the VLDL-LDL cascade, we examined whether these two patterns of lipoprotein diameter were associated with differences across two lipoprotein lipase (LPL) gene variants: D9N (rs1801177) and S447X (rs328).
FINDINGS - Mixed linear models that controlled for age, sex, center of data collection, and family pedigree revealed no differences between the two groups for the D9N polymorphism (P = .36). However, group 2 contained significantly more carriers (25%) of the 447X variant than group 1 (14%; P = .04).
CONCLUSIONS - This was the first study this kind to show an association between LPL and large VLDL particle size within the MetS, a pattern associated with higher IR. Future work should extend this to larger samples to confirm these findings, and examine the long term outcomes of those with this lipoprotein diameter pattern.
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22 MeSH Terms
Genetic determinants of lipid traits in diverse populations from the population architecture using genomics and epidemiology (PAGE) study.
Dumitrescu L, Carty CL, Taylor K, Schumacher FR, Hindorff LA, Ambite JL, Anderson G, Best LG, Brown-Gentry K, Bůžková P, Carlson CS, Cochran B, Cole SA, Devereux RB, Duggan D, Eaton CB, Fornage M, Franceschini N, Haessler J, Howard BV, Johnson KC, Laston S, Kolonel LN, Lee ET, MacCluer JW, Manolio TA, Pendergrass SA, Quibrera M, Shohet RV, Wilkens LR, Haiman CA, Le Marchand L, Buyske S, Kooperberg C, North KE, Crawford DC
(2011) PLoS Genet 7: e1002138
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Continental Population Groups, Female, Gene Frequency, Genetics, Population, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Lipid Metabolism, Lipoproteins, HDL, Lipoproteins, LDL, Male, Middle Aged, Molecular Epidemiology, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, Triglycerides, Young Adult
Show Abstract · Added December 10, 2013
For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%, 64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.
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22 MeSH Terms
Effects of fenofibrate on plasma oxidized LDL and 8-isoprostane in a sub-cohort of GOLDN participants.
Dong Y, Steffen BT, Cao J, Tsai AK, Ordovas J, Straka R, Zhou X, Kabagambe E, Hanson NQ, Arnett D, Tsai MY
(2011) Atherosclerosis 214: 422-5
MeSH Terms: Atherosclerosis, Biomarkers, Cohort Studies, Dinoprost, Fenofibrate, Genetic Predisposition to Disease, Humans, Hypolipidemic Agents, Lipoproteins, LDL, Oxidative Stress, Time Factors, Treatment Outcome, Triglycerides, United States
Show Abstract · Added April 23, 2015
BACKGROUND - Fenofibrate significantly reduces circulating triglyceride (TG) concentrations, particularly in individuals with elevated levels. The purpose of the current study was to determine whether fenofibrate treatment reduces markers of oxidative stress, oxidized low density lipoprotein (ox-LDL) and 8-isoprostane (8-isoP), in a manner similar to TG where those with the highest levels show the greatest reductions.
MATERIALS/METHODS - The concentrations of TG, 8-isoP, and ox-LDL were measured in plasma before and after 3 weeks of fenofibrate treatment (160 mg/d) in a sub-cohort (n=187) of the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study.
RESULTS - Data were divided into tertiles as determined by pre-treatment values of the respective target. Fenofibrate treatment resulted in significant reductions in TG concentrations by 24.2% (p<0.0001), 41.9% (p < 0.0001), and 46.6% (p < 0.0001) in tertiles 1, 2, and 3, respectively. Significant reductions were also observed in ox-LDL of 7.2% (p=0.0096), 8.5% (p = 0.0019) and 12.1% (p < 0.0001) in tertiles 1, 2, and 3, respectively. Finally, fenofibrate treatment resulted in a 32.7% increase (p=0.0201) in 8-isoP levels in tertile 1, but a significant decrease of 34.4% (p < 0.0001) in tertile 3.
CONCLUSIONS - This study is the largest to date to demonstrate that fenofibrate reduces oxidative stress and the first to show a suppressive effect on 8-isoP levels in individuals with a high oxidative burden following short term (3 wk) drug therapy. Those with the highest baseline levels of ox-LDL and 8-isoP showed the greatest reductions following fenofibrate treatment. Given the role of oxidative stress in atherosclerosis and coronary heart disease, our observations may partially explain the efficacy of fenofibrate in reducing cardiovascular events in select patients.
Published by Elsevier Ireland Ltd.
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14 MeSH Terms
The inhibitory FcγRIIb modulates the inflammatory response and influences atherosclerosis in male apoE(-/-) mice.
Mendez-Fernandez YV, Stevenson BG, Diehl CJ, Braun NA, Wade NS, Covarrubias R, van Leuven S, Witztum JL, Major AS
(2011) Atherosclerosis 214: 73-80
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, Aorta, Apolipoproteins E, Atherosclerosis, B-Lymphocytes, Cytokines, Enzyme-Linked Immunosorbent Assay, Inflammation, Lipoproteins, LDL, Male, Mice, Mice, Transgenic, Receptors, IgG
Show Abstract · Added February 11, 2014
BACKGROUND - Atherosclerosis is widely accepted as an inflammatory disease involving both innate and adaptive immunity. B cells and/or antibodies have previously been shown to play a protective role against atherosclerosis. Aside from their ability to bind to antigens, antibodies can influence inflammatory responses by interacting with various Fcγ receptors on the surface of antigen presenting cells. Although studies in mice have determined that stimulatory Fcγ receptors contribute to atherosclerosis, the role of the inhibitory Fcγ receptor IIb (FcγRIIb) has only recently been investigated.
METHODS AND RESULTS - To determine the importance of FcγRIIb in modulating the adaptive immune response to hyperlipidemia, we generated FcγRIIb-deficient mice on the apoE-deficient background (apoE/FcγRIIb(-/-)). We report that male apoE/FcγRIIb(-/-) mice develop exacerbated atherosclerosis that is independent of lipid levels, and is characterized by increased antibody titers to modified LDL and pro-inflammatory cytokines in the aorta.
CONCLUSIONS - These findings suggest that antibodies against atherosclerosis-associated antigens partially protect against atherosclerosis in male apoE(-/-) mice by conveying inhibitory signals through the FcγRIIb that downregulate pro-inflammatory signaling via other immune receptors. These data are the first to describe a significant in vivo effect for FcγRIIb in modulating the cytokine response in the aorta in male apoE(-/-) mice.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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15 MeSH Terms
Ascorbic acid prevents increased endothelial permeability caused by oxidized low density lipoprotein.
May JM, Qu ZC
(2010) Free Radic Res 44: 1359-68
MeSH Terms: Antioxidants, Ascorbic Acid, Capillary Permeability, Cell Line, Endothelium, Vascular, Humans, Lipoproteins, LDL, Oxidative Stress
Show Abstract · Added December 5, 2013
Abstract Mildly oxidized low density lipoprotein (mLDL) acutely increases the permeability of the vascular endothelium to molecules that would not otherwise cross the barrier. This study has shown that ascorbic acid tightens the permeability barrier in the endothelial barrier in cells, so this work tested whether it might prevent the increase in endothelial permeability due to mLDL. Treatment of EA.hy926 endothelial cells with mLDL decreased intracellular GSH and activated the cells to further oxidize the mLDL. mLDL also increased endothelial permeability over 2 h to both inulin and ascorbate in cells cultured on semi-permeable filters. This effect was blocked by microtubule and microfilament inhibitors, but not by chelation of intracellular calcium. Intracellular ascorbate both prevented and reversed the mLDL-induced increase in endothelial permeability, an effect mimicked by other cell-penetrant antioxidants. These results suggest a role for endothelial cell ascorbate in ameliorating an important facet of endothelial dysfunction caused by mLDL.
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8 MeSH Terms
miR-33 links SREBP-2 induction to repression of sterol transporters.
Marquart TJ, Allen RM, Ory DS, Baldán A
(2010) Proc Natl Acad Sci U S A 107: 12228-32
MeSH Terms: 5' Untranslated Regions, ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Animals, Base Sequence, Cell Line, Cholesterol, Cholesterol, HDL, Gene Expression Regulation, Humans, Lipoproteins, LDL, Male, Mice, Mice, Inbred C57BL, MicroRNAs, Molecular Sequence Data, RNA, Messenger, Receptors, LDL, Response Elements, Reverse Transcriptase Polymerase Chain Reaction, Sterol Regulatory Element Binding Protein 2, Transcriptional Activation, Transfection
Show Abstract · Added February 12, 2016
The sterol regulatory element binding protein 2 (SREBP-2) and the liver X receptor (LXR) control antagonistic transcriptional programs that stimulate cellular cholesterol uptake and synthesis, and cholesterol efflux, respectively. The clinical importance of SREBP-2 is revealed in patients with hypercholesterolemia treated with statins, which reduce low-density lipoprotein (LDL) cholesterol levels by increasing hepatic expression of SREBP-2 and its target, the LDL receptor. Here we show that miR-33 is encoded within SREBP-2 and that both mRNAs are coexpressed. We also identify sequences in the 3' UTR of ABCA1 and ABCG1, sterol transporter genes both previously shown to be regulated by LXR, as targets for miR-33-mediated silencing. Our data show that LXR-dependent cholesterol efflux to both ApoAI and serum is ameliorated by miR-33 overexpression and, conversely, stimulated by miR-33 silencing. Finally, we show that ABCA1 mRNA and protein and plasma HDL levels decline after hepatic overexpression of miR-33, whereas they increase after hepatic miR-33 silencing. These results suggest novel ways to manage hypercholesterolemic patients.
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24 MeSH Terms