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Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moiety and : Implication in atherosclerosis.
Lu J, Guo S, Xue X, Chen Q, Ge J, Zhuo Y, Zhong H, Chen B, Zhao M, Han W, Suzuki T, Zhu M, Xia L, Schneider C, Blackwell TS, Porter NA, Zheng L, Tsimikas S, Yin H
(2017) J Biol Chem 292: 5378-5391
MeSH Terms: Animals, Anti-Inflammatory Agents, Antioxidants, Atherosclerosis, Cyclopentanes, Foam Cells, Humans, Inflammation, Lipoproteins, LDL, Macrophages, Mice, Mice, Transgenic, Oxidative Stress, Phospholipids, Signal Transduction
Show Abstract · Added March 29, 2017
Oxidative stress and inflammation are two major contributing factors to atherosclerosis, a leading cause of cardiovascular disease. Oxidation of phospholipids on the surface of low density lipoprotein (LDL) particles generated under oxidative stress has been associated with the progression of atherosclerosis, but the underlying molecular mechanisms remain poorly defined. We identified a novel series of oxidation products containing the cyclopentenone moiety, termed deoxy-A/J-isoprostanes-phosphocholine, from 1-palmitoyl-2-arachidonoyl--glycero-3-phosphocholine using mass spectrometry and by comparison to a chemically synthesized standard. Transcriptomic analysis (RNA-seq) demonstrated that these compounds affected >200 genes in bone marrow-derived macrophages, and genes associated with inflammatory and anti-oxidative responses are among the top 5 differentially expressed. To further investigate the biological relevance of these novel oxidized phospholipids in atherosclerosis, we chemically synthesized a representative compound 1-palmitoyl-2-15-deoxy-δ-12,14-prostaglandin J--glycero-3-phosphocholine (15d-PGJ-PC) and found that it induced anti-inflammatory and anti-oxidant responses in macrophages through modulation of NF-κB, peroxisome proliferator-activated receptor γ (PPARγ), and Nrf2 pathways; this compound also showed potent anti-inflammatory properties in a mice model of LPS-induced systematic inflammatory response syndrome. Additionally, 15d-PGJ-PC inhibited macrophage foam cell formation, suggesting a beneficial role against atherosclerosis. These properties were consistent with decreased levels of these compounds in the plasma of patients with coronary heart disease compared with control subjects. Our findings uncovered a novel molecular mechanism for the negative regulation of inflammation and positive enhancement of anti-oxidative responses in macrophages by these oxidized phospholipids in LDL in the context of atherosclerosis.
© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
1 Communities
1 Members
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15 MeSH Terms
Hepcidin-ferroportin axis controls toll-like receptor 4 dependent macrophage inflammatory responses in human atherosclerotic plaques.
Habib A, Polavarapu R, Karmali V, Guo L, Van Dam R, Cheng Q, Akahori H, Saeed O, Nakano M, Pachura K, Hong CC, Shin E, Kolodgie F, Virmani R, Finn AV
(2015) Atherosclerosis 241: 692-700
MeSH Terms: Animals, Antigens, CD, Antigens, Differentiation, Myelomonocytic, Cation Transport Proteins, Foam Cells, Haptoglobins, Hemoglobins, Hepcidins, Humans, Inflammation, Iron, Lipopolysaccharides, Lipoproteins, LDL, Macrophages, Macrophages, Peritoneal, Male, Membrane Microdomains, Mice, Mice, Inbred C57BL, Mice, Knockout, Myeloid Differentiation Factor 88, Plaque, Atherosclerotic, Receptors, Cell Surface, Signal Transduction, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha
Show Abstract · Added July 7, 2015
OBJECTIVES - Toll-like Receptor 4 (TLR4) is implicated in modulating inflammatory cytokines though its role in atherosclerosis remains uncertain. We have recently described a non-foam cell macrophage phenotype driven by ingestion of hemoglobin:haptoglobin complexes (HH), via the scavenger receptor CD163, characterized by reduced inflammatory cytokine production. In this study, we examined the role of iron metabolism in modulating TLR4 signaling in these cells.
METHODS AND RESULTS - Areas in human atherosclerotic plaque with non-foam cell, CD163 positive macrophages demonstrated reduced expression of tumor necrosis factor alpha (TNF-α) and interferon-beta (INF-β) compared to foam cells. Human macrophages differentiated in hemoglobin:haptoglobin (HH) complexes expressed the CD163 positive non-foam cell phenotype and demonstrated significantly less TNF-α and INF-β compared to control macrophages when exposed to oxidized LDL (oxLDL) or lipopolysaccharide (LPS). LPS stimulated expression of TNF-α and INF-β could be restored in HH macrophages by pretreatment with hepcidin, an endogenous suppressor of ferroportin1 (FPN), or by genetic suppression of FPN in macrophages derived from myeloid specific FPN knockout mice. LPS stimulated control macrophages demonstrated increase in TLR4 trafficking to lipid rafts; this response was suppressed in HH macrophages but was restored upon pretreatment with hepcidin. Using a pharmacologic hepcidin suppressor, we observed a decrease in cytokine expression and TLR4-lipid raft trafficking in LPS-stimulated in a murine macrophage model.
CONCLUSION - TLR4 dependent macrophage signaling is controlled via hepcidin-ferroportin1 axis by influencing TLR4-lipid raft interactions. Pharmacologic manipulation of iron metabolism may represent a promising approach to limiting TLR4-mediated inflammatory responses.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
1 Communities
1 Members
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26 MeSH Terms
Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses.
Spann NJ, Garmire LX, McDonald JG, Myers DS, Milne SB, Shibata N, Reichart D, Fox JN, Shaked I, Heudobler D, Raetz CR, Wang EW, Kelly SL, Sullards MC, Murphy RC, Merrill AH, Brown HA, Dennis EA, Li AC, Ley K, Tsimikas S, Fahy E, Subramaniam S, Quehenberger O, Russell DW, Glass CK
(2012) Cell 151: 138-52
MeSH Terms: Animals, Atherosclerosis, Cholesterol, Desmosterol, Fatty Acids, Foam Cells, Gene Knockdown Techniques, Leukocytes, Mononuclear, Lipid Metabolism, Male, Mice, Mice, Inbred C57BL, Receptors, LDL, Sterol Regulatory Element Binding Proteins, Transcriptome
Show Abstract · Added March 21, 2013
Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant changes in hundreds of lipid species and unexpected suppression, rather than activation, of inflammatory gene expression. We provide evidence that regulated accumulation of desmosterol underlies many of the homeostatic responses, including activation of LXR target genes, inhibition of SREBP target genes, selective reprogramming of fatty acid metabolism, and suppression of inflammatory-response genes, observed in macrophage foam cells. These observations suggest that macrophage activation in atherosclerotic lesions results from extrinsic, proinflammatory signals generated within the artery wall that suppress homeostatic and anti-inflammatory functions of desmosterol.
Copyright © 2012 Elsevier Inc. All rights reserved.
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1 Members
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15 MeSH Terms
Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis.
Saeed O, Otsuka F, Polavarapu R, Karmali V, Weiss D, Davis T, Rostad B, Pachura K, Adams L, Elliott J, Taylor WR, Narula J, Kolodgie F, Virmani R, Hong CC, Finn AV
(2012) Arterioscler Thromb Vasc Biol 32: 299-307
MeSH Terms: ATP Binding Cassette Transporter 1, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP-Binding Cassette Transporters, Animals, Antimicrobial Cationic Peptides, Apolipoproteins E, Atherosclerosis, Bone Morphogenetic Proteins, Cell Differentiation, Cholesterol, Disease Models, Animal, Foam Cells, Hepcidins, Iron, Lipoproteins, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Pyrazoles, Pyrimidines, Signal Transduction
Show Abstract · Added August 19, 2012
OBJECTIVE - We recently reported that lowering of macrophage free intracellular iron increases expression of cholesterol efflux transporters ABCA1 and ABCG1 by reducing generation of reactive oxygen species. In this study, we explored whether reducing macrophage intracellular iron levels via pharmacological suppression of hepcidin can increase macrophage-specific expression of cholesterol efflux transporters and reduce atherosclerosis.
METHODS AND RESULTS - To suppress hepcidin, increase expression of the iron exporter ferroportin, and reduce macrophage intracellular iron, we used a small molecule inhibitor of bone morphogenetic protein (BMP) signaling, LDN 193189 (LDN). LDN (10 mg/kg IP b.i.d.) was administered to mice, and its effects on atherosclerosis, intracellular iron, oxidative stress, lipid efflux, and foam cell formation were measured in plaques and peritoneal macrophages. Long-term LDN administration to apolipoprotein E-/- mice increased ABCA1 immunoreactivity within intraplaque macrophages by 3.7-fold (n=8; P=0.03), reduced Oil Red O-positive lipid area by 50% (n=8; P=0.02), and decreased total plaque area by 43% (n=8; P=0.001). LDN suppressed liver hepcidin transcription and increased macrophage ferroportin, lowering intracellular iron and hydrogen peroxide production. LDN treatment increased macrophage ABCA1 and ABCG1 expression, significantly raised cholesterol efflux to ApoA-1, and decreased foam cell formation. All preceding LDN-induced effects on cholesterol efflux were reversed by exogenous hepcidin administration, suggesting modulation of intracellular iron levels within macrophages as the mechanism by which LDN triggers these effects.
CONCLUSIONS - These data suggest that pharmacological manipulation of iron homeostasis may be a promising target to increase macrophage reverse cholesterol transport and limit atherosclerosis.
1 Communities
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23 MeSH Terms
Cytoskeleton disruption in J774 macrophages: consequences for lipid droplet formation and cholesterol flux.
Weibel GL, Joshi MR, Jerome WG, Bates SR, Yu KJ, Phillips MC, Rothblat GH
(2012) Biochim Biophys Acta 1821: 464-72
MeSH Terms: Actin Cytoskeleton, Animals, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Cholesterol Esters, Cytochalasin D, Cytoskeletal Proteins, Foam Cells, Hydrolysis, Lipid Metabolism, Mice, Organelle Size, Organelles, Proteome, Sterol Esterase, Thiazolidines, Triglycerides
Show Abstract · Added December 10, 2013
Macrophages store excess unesterified cholesterol (free, FC) in the form of cholesteryl ester (CE) in cytoplasmic lipid droplets. The hydrolysis of droplet-CE in peripheral foam cells is critical to HDL-promoted reverse cholesterol transport because it represents the first step in cellular cholesterol clearance, as only FC is effluxed from cells to HDL. Cytoplasmic lipid droplets move within the cell utilizing the cytoskeletal network, but, little is known about the influence of the cytoskeleton on lipid droplet formation. To understand this role we employed cytochalasin D (cyt.D) to promote actin depolymerization in J774 macrophages. Incubating J774 with acetylated LDL creates foam cells having a 4-fold increase in cellular cholesterol content (30-40% cholesterol present as cholesteryl ester (CE)) in cytoplasmic droplets. Lipid droplets formed in the presence of cyt.D are smaller in diameter. CE-deposition and -hydrolysis are decreased when cells are cholesterol-enriched in the presence of cyt.D or latrunculin A, another cytoskeleton disrupting agent. However, when lipid droplets formed in the presence of cyt.D are isolated and incubated with an exogenous CE hydrolase, the CE is more rapidly metabolized compared to droplets from control cells. This is apparently due to the smaller size and altered lipid composition of the droplets formed in the presence of cyt.D. Cytoskeletal proteins found on CE droplets influence droplet lipid composition and maturation in model foam cells. In J774 macrophages, cytoskeletal proteins are apparently involved in facilitating the interaction of lipid droplets and a cytosolic neutral CE hydrolase and may play a role in foam cell formation. 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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1 Members
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17 MeSH Terms
Foamy cell angiosarcoma: a rare and deceptively bland variant of cutaneous angiosarcoma.
Tatsas AD, Keedy VL, Florell SR, Simpson JF, Coffin CM, Kelley MC, Cates JM
(2010) J Cutan Pathol 37: 901-6
MeSH Terms: Aged, Diagnosis, Differential, Foam Cells, Forehead, Granuloma, Head and Neck Neoplasms, Hemangiosarcoma, Humans, Male, Shoulder, Skin Neoplasms, Xanthomatosis, Young Adult
Show Abstract · Added March 15, 2013
Cutaneous angiosarcoma can sometimes mimic other benign and malignant lesions, thereby presenting a difficult differential diagnosis. In the two cases of cutaneous angiosarcoma presented herein, extensive foamy cell alteration of tumor cells resembled a reactive xanthogranulomatous process. Foamy cell angiosarcoma is an unusual and deceptively benign morphologic variant of cutaneous angiosarcoma. Critical features for diagnosis include the presence of a deep, permeative, sometimes 'scaffolding' growth pattern and subtle areas of vascular formation.
0 Communities
4 Members
0 Resources
13 MeSH Terms
Nitro-fatty acids reduce atherosclerosis in apolipoprotein E-deficient mice.
Rudolph TK, Rudolph V, Edreira MM, Cole MP, Bonacci G, Schopfer FJ, Woodcock SR, Franek A, Pekarova M, Khoo NK, Hasty AH, Baldus S, Freeman BA
(2010) Arterioscler Thromb Vasc Biol 30: 938-45
MeSH Terms: Actins, Animals, Anti-Inflammatory Agents, Antioxidants, Aortic Diseases, Apolipoproteins E, Atherosclerosis, Cell Adhesion Molecules, Cells, Cultured, Chemokine CCL2, Collagen, Disease Models, Animal, Dose-Response Relationship, Drug, Foam Cells, Injections, Subcutaneous, Lipoproteins, LDL, Male, Mice, Mice, Knockout, Oleic Acids, Oxidants, Oxidative Stress, Phosphorylation, STAT1 Transcription Factor, Signal Transduction
Show Abstract · Added March 27, 2013
OBJECTIVE - Inflammatory processes and foam cell formation are key determinants in the initiation and progression of atherosclerosis. Electrophilic nitro-fatty acids, byproducts of nitric oxide- and nitrite-dependent redox reactions of unsaturated fatty acids, exhibit antiinflammatory signaling actions in inflammatory and vascular cell model systems. The in vivo action of nitro-fatty acids in chronic inflammatory processes such as atherosclerosis remains to be elucidated.
METHODS AND RESULTS - Herein, we demonstrate that subcutaneously administered 9- and 10-nitro-octadecenoic acid (nitro-oleic acid) potently reduced atherosclerotic lesion formation in apolipoprotein E-deficient mice. Nitro-fatty acids did not modulate serum lipoprotein profiles. Immunostaining and gene expression analyses revealed that nitro-oleic acid attenuated lesion formation by suppressing tissue oxidant generation, inhibiting adhesion molecule expression, and decreasing vessel wall infiltration of inflammatory cells. In addition, nitro-oleic acid reduced foam cell formation by attenuating oxidized low-density lipoprotein-induced phosphorylation of signal transducer and activator of transcription-1, a transcription factor linked to foam cell formation in atherosclerotic plaques. Atherosclerotic lesions of nitro-oleic acid-treated animals also showed an increased content of collagen and alpha-smooth muscle actin, suggesting conferral of higher plaque stability.
CONCLUSION - These results reveal the antiatherogenic actions of electrophilic nitro-fatty acids in a murine model of atherosclerosis.
0 Communities
1 Members
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25 MeSH Terms
Renal dysfunction potentiates foam cell formation by repressing ABCA1.
Zuo Y, Yancey P, Castro I, Khan WN, Khan W, Motojima M, Ichikawa I, Fogo AB, Linton MF, Fazio S, Kon V
(2009) Arterioscler Thromb Vasc Biol 29: 1277-82
MeSH Terms: ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Angiotensin II Type 1 Receptor Blockers, Animals, Apolipoproteins E, Atherosclerosis, Cells, Cultured, Cholesterol, Disease Models, Animal, Down-Regulation, Female, Foam Cells, Kidney Diseases, Losartan, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Nephrectomy
Show Abstract · Added December 10, 2013
OBJECTIVE - Patients with chronic kidney disease (CKD) have the highest risk for atherosclerotic cardiovascular disease (CVD). Current interventions have been insufficiently effective in lessening excess incidence and mortality from CVD in CKD patients versus other high-risk groups. The mechanisms underlying the heightened risk remain obscure but may relate to differences in CKD-induced atherogenesis, including perturbation of macrophage cholesterol trafficking.
METHODS AND RESULTS - We examined the impact of renal dysfunction on macrophage cholesterol homeostasis in the apoE(-/-) mouse model of atherosclerosis. Renal impairment induced by uninephrectomy dramatically increased macrophage cholesterol content, linked to striking impairment of macrophage cholesterol efflux. This blunted efflux was associated with downregulation of the cholesterol transporter ATP-binding cassette transporter A1 (ABCA1) and activation of the nuclear factor-kappa B (NF-kappaB). Treatment with the angiotensin receptor blocker (ARB) losartan decreased NF-kappaB and restored cholesterol efflux.
CONCLUSIONS - Our findings show that mild renal dysfunction perturbs macrophage lipid homeostasis by inhibiting cholesterol efflux, mediated by decreased ABCA1 transporter and activation of NF-kappaB, and that ARB can restore cholesterol efflux.
2 Communities
5 Members
0 Resources
19 MeSH Terms
Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells.
Ullery-Ricewick JC, Cox BE, Griffin EE, Jerome WG
(2009) J Lipid Res 50: 2014-26
MeSH Terms: Cell Line, Cholesterol Esters, Foam Cells, Humans, Lipoproteins, LDL, Lysosomes, Microscopy, Electron, Triglycerides
Show Abstract · Added December 10, 2013
In late-stage atherosclerosis, much of the cholesterol in macrophage foam cells resides within enlarged lysosomes. Similarly, human macrophages incubated in vitro with modified LDLs contain significant amounts of lysosomal free cholesterol and cholesteryl ester (CE), which disrupts lysosomal function similar to macrophages in atherosclerotic lesions. The lysosomal cholesterol cannot be removed, even in the presence of strong efflux promoters. Thus, efflux of sterol is prevented. In the artery wall, foam cells interact with triglyceride-rich particles (TRPs) in addition to modified LDLs. Little is known about how TRP metabolism affects macrophage cholesterol. Therefore, we explored the effect of TRP on intracellular CE metabolism. Triglyceride (TG), delivered to lysosomes in TRP, reduced CE accumulation by 50%. Increased TG levels within the cell, particularly within lysosomes, correlated with reductions in CE content. The volume of cholesterol-engorged lysosomes decreased after TRP treatment, indicating cholesterol was cleared. Lysosomal TG also reduced the cholesterol-induced inhibition of lysosomal acidification allowing lysosomes to remain active. Enhanced degradation and clearance of CE may be explained by movement of cholesterol out of the lysosome to sites where it is effluxed. Thus, our results show that introduction of TG into CE-laden foam cells influences CE metabolism and, potentially, atherogenesis.-Ullery-Ricewick, J. C., B. E. Cox, E. E. Griffin, and W. G. Jerome. Triglyceride alters lysosomal cholesterol ester metabolism in cholesteryl ester-laden macrophage foam cells.
0 Communities
1 Members
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8 MeSH Terms
Lysosomal cholesterol accumulation inhibits subsequent hydrolysis of lipoprotein cholesteryl ester.
Jerome WG, Cox BE, Griffin EE, Ullery JC
(2008) Microsc Microanal 14: 138-49
MeSH Terms: Cell Line, Cholesterol, Cholesterol Esters, Foam Cells, Humans, Hydrolysis, Lipoproteins, Lysosomes, Macrophages
Show Abstract · Added December 10, 2013
Human macrophages incubated for prolonged periods with mildly oxidized LDL (oxLDL) or cholesteryl ester-rich lipid dispersions (DISP) accumulate free and esterified cholesterol within large, swollen lysosomes similar to those in foam cells of atherosclerosis. The cholesteryl ester (CE) accumulation is, in part, the result of inhibition of lysosomal hydrolysis due to increased lysosomal pH mediated by excessive lysosomal free cholesterol (FC). To determine if the inhibition of hydrolysis was long lived and further define the extent of the lysosomal defect, we incubated THP-1 macrophages with oxLDL or DISP to produce lysosome sterol engorgement and then chased with acetylated LDL (acLDL). Unlike oxLDL or DISP, CE from acLDL normally is hydrolyzed rapidly. Three days of incubation with oxLDL or DISP produced an excess of CE in lipid-engorged lysosomes, indicative of inhibition. After prolonged oxLDL or DISP pretreatment, subsequent hydrolysis of acLDL CE was inhibited. Coincident with the inhibition, the lipid-engorged lysosomes failed to maintain an acidic pH during both the initial pretreatment and subsequent acLDL incubation. This indicates that the alterations in lysosomes were general, long lived, and affected subsequent lipoprotein metabolism. This same phenomenon, occurring within atherosclerotic foam cells, could significantly affect lesion progression.
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9 MeSH Terms