14 results on '"Major, Amy S."'
Search Results
2. Loss of Macrophage Low-Density Lipoprotein Receptor--Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.
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Lin Zhu, Giunzioni, Ilaria, Tavori, Hagai, Covarrubias, Roman, Lei Ding, Youmin Zhang, Ormseth, Michelle, Major, Amy S., Stafford, John M., Linton, MacRae F., and Fazio, Sergio
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- 2016
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3. Deletion of Macrophage LDL Receptor-Related Protein Increases Atherogenesis in the Mouse.
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Overton, Cheryl D., Yancey, Patricia G., Major, Amy S., Linton, MacRae F., and Fazio, Sergio
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- 2007
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4. Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1.
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Su YR, Dove DE, Major AS, Hasty AH, Boone B, Linton MF, Fazio S, Su, Yan Ru, Dove, Dwayne E, Major, Amy S, Hasty, Alyssa H, Boone, Branden, Linton, MacRae F, and Fazio, Sergio
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- 2005
5. What Fans the Fire.
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Major, Amy S. and Harrison, David G.
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ATHEROSCLEROSIS , *TYPE 2 diabetes , *LECTINS , *MACROPHAGES , *LOW density lipoproteins , *CELLULAR signal transduction - Abstract
The authors discusses a study by M. Xia et al on the role of a specific activating molecule NK cell lectin-like receptor subfamily K (NKG2D) in atherosclerosis and type 2 diabetes. The researchers demonstrated that low-density lipoprotein (LDL), oxidized LDL and advanced glycation end products upregulate the Rae-1 expression on macrophages. They also indicate that poroducts associated with atherosclerosis and diabetes may be responsible for providing signals of cellular stress and damage.
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- 2011
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6. Expanding the Therapeutic Frontier in Atherosclerosis.
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Major, Amy S.
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- 2013
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7. Humanizing the Problem of Transplant Vasculopathy.
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Méndez-Fernández, Yanice V. and Major, Amy S.
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- 2012
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8. Oxidized Phospholipid oxPAPC Alters Regulatory T-Cell Differentiation and Decreases Their Protective Function in Atherosclerosis in Mice.
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Appleton BD, Palmer SA, Smith HP, Stephens LE, and Major AS
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- Mice, Animals, T-Lymphocytes, Regulatory, Interferon-gamma metabolism, Cell Differentiation, Phospholipids metabolism, Atherosclerosis genetics, Atherosclerosis prevention & control
- Abstract
Background: Regulatory T cells (T
regs ) are protective in atherosclerosis but reduced during disease progression due to cell death and loss of stability. However, the mechanisms of Treg dysfunction remain unknown. Oxidized phospholipids are abundant in atherosclerosis and can activate innate immune cells, but little is known regarding their impact on T cells. Given Treg loss during atherosclerosis progression and oxidized phospholipid levels in the plaque microenvironment, we investigated whether oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (oxPAPC), an oxidized phospholipid associated with atherosclerotic plaques, alters Treg differentiation and function., Methods: CD4+ T cells were polarized to Treg , T helper (Th) 1, and Th17 cells with or without oxPAPC and assessed by flow cytometry. Gene expression in oxPAPC-treated Tregs was analyzed by bulk RNA sequencing. Functional studies of oxPAPC-induced Tregs were performed by coculturing Tregs with CellTrace Violet-labeled cells in vitro, and by adoptively transferring Tregs to hyperlipidemic Ldlr-/- mice to measure atherosclerosis progression., Results: Compared with controls, oxPAPC-treated Tregs were less viable, but surviving cells expressed higher levels of the Th1-associated markers T-bet, CXCR3, and IFN (interferon)-γ. Th1 and Th17 skewing cultures were unaltered by oxPAPC. IFN-γ is linked to Treg instability, thus Treg polarization experiments were repeated using Ifngr1-/- CD4+ T cells. IFNγR1 (INF gamma receptor 1) deficiency did not improve cell viability in oxPAPC-treated Tregs ; however, T-bet and IFN-γ expression was not increased in surviving cells suggesting a role for IFN-γsignaling. OxPAPC-treated Tregs were less suppressive in vitro, and adoptive transfer studies in hyperlipidemic Ldlr-/- mice showed that oxPAPC-induced Tregs possessed altered tissue homing and were insufficient to inhibit atherosclerosis progression., Conclusions: OxPAPC elicits Treg -specific changes altering Treg differentiation and inducing a Th1-like phenotype in surviving cells partially through IFN-γ signaling. This is biologically relevant as oxPAPC-treated Tregs do not reduce atherosclerosis progression in Ldlr-/- mice. This study supports the role of oxidized phospholipids in negatively impacting Treg differentiation and atheroprotective function., Competing Interests: Disclosures None.- Published
- 2023
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9. Loss of Macrophage Low-Density Lipoprotein Receptor-Related Protein 1 Confers Resistance to the Antiatherogenic Effects of Tumor Necrosis Factor-α Inhibition.
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Zhu L, Giunzioni I, Tavori H, Covarrubias R, Ding L, Zhang Y, Ormseth M, Major AS, Stafford JM, Linton MF, and Fazio S
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- Animals, Antigens, Ly metabolism, Aorta metabolism, Aorta pathology, Aortic Diseases genetics, Aortic Diseases metabolism, Aortic Diseases pathology, Apolipoproteins E deficiency, Apolipoproteins E genetics, Apoptosis drug effects, Atherosclerosis genetics, Atherosclerosis metabolism, Atherosclerosis pathology, Bone Marrow Transplantation, Cell Movement drug effects, Diet, High-Fat, Disease Models, Animal, Female, Genetic Predisposition to Disease, Low Density Lipoprotein Receptor-Related Protein-1, Macrophages metabolism, Macrophages pathology, Mice, Knockout, Monocytes drug effects, Monocytes metabolism, Necrosis, Phenotype, Plaque, Atherosclerotic, Receptors, LDL deficiency, Receptors, LDL genetics, Signal Transduction drug effects, Tumor Necrosis Factor-alpha metabolism, Tumor Suppressor Proteins deficiency, Tumor Suppressor Proteins genetics, Whole-Body Irradiation, Adalimumab pharmacology, Anti-Inflammatory Agents pharmacology, Aorta drug effects, Aortic Diseases prevention & control, Atherosclerosis prevention & control, Drug Resistance genetics, Macrophages drug effects, Receptors, LDL metabolism, Tumor Necrosis Factor-alpha antagonists & inhibitors, Tumor Suppressor Proteins metabolism
- Abstract
Objective: Antiatherosclerotic effects of tumor necrosis factor-α (TNF-α) blockade in patients with systemic inflammatory states are not conclusively demonstrated, which suggests that effects depend on the cause of inflammation. Macrophage LRP1 (low-density lipoprotein receptor-related protein 1) and apoE contribute to inflammation through different pathways. We studied the antiatherosclerosis effects of TNF-α blockade in hyperlipidemic mice lacking either LRP1 (MΦLRP1(-/-)) or apoE from macrophages., Approach and Results: Lethally irradiated low-density lipoprotein receptor (LDLR)(-/-) mice were reconstituted with bone marrow from either wild-type, MΦLRP1(-/-), apoE(-/-) or apoE(-/-)/MΦLRP1(-/-)(DKO) mice, and then treated with the TNF-α inhibitor adalimumab while fed a Western-type diet. Adalimumab reduced plasma TNF-α concentration, suppressed blood ly6C(hi) monocyte levels and their migration into the lesion, and reduced lesion cellularity and inflammation in both wild-type→LDLR(-/-) and apoE(-/-)→LDLR(-/-) mice. Overall, adalimumab reduced lesion burden by 52% to 57% in these mice. Adalimumab reduced TNF-α and blood ly6C(hi) monocyte levels in MΦLRP1(-/-)→LDLR(-/-) and DKO→LDLR(-/-) mice, but it did not suppress ly6C(hi) monocyte migration into the lesion or atherosclerosis progression., Conclusions: Our results show that TNF-α blockade exerts antiatherosclerotic effects that are dependent on the presence of macrophage LRP1., (© 2016 American Heart Association, Inc.)
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- 2016
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10. Development of spontaneous anergy in invariant natural killer T cells in a mouse model of dyslipidemia.
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Braun NA, Mendez-Fernandez YV, Covarrubias R, Porcelli SA, Savage PB, Yagita H, Van Kaer L, and Major AS
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- Animals, Antigen-Presenting Cells immunology, Antigens, Surface metabolism, Apolipoproteins E deficiency, Apolipoproteins E genetics, Apoptosis Regulatory Proteins metabolism, Cell Proliferation, Cells, Cultured, Chronic Disease, Cytokines metabolism, Dendritic Cells immunology, Disease Models, Animal, Galactosylceramides administration & dosage, Hyperlipidemias genetics, Injections, Intraperitoneal, Interleukin-2 metabolism, Lymphocyte Count, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, NK Cell Lectin-Like Receptor Subfamily A metabolism, Natural Killer T-Cells drug effects, Phenotype, Programmed Cell Death 1 Receptor, Receptors, Antigen, T-Cell metabolism, Time Factors, Clonal Anergy, Hyperlipidemias immunology, Lymphocyte Activation drug effects, Natural Killer T-Cells immunology
- Abstract
Objective: In this study, we investigated whether dyslipidemia-associated perturbed invariant natural killer T (iNKT) cell function is due to intrinsic changes in iNKT cells or defects in the ability of antigen-presenting cells to activate iNKT cells., Methods and Results: We compared iNKT cell expansion and cytokine production in C57BL/6J (B6) and apolipoprotein E-deficient (apoE(-/-)) mice. In response to in vivo stimulation with alpha-galactosylceramide, a prototypic iNKT cell glycolipid antigen, apoE(-/-) mice showed significantly decreased splenic iNKT cell expansion at 3 days after injection, a profile associated with iNKT cell anergy due to chronic stimulation. This decrease in expansion and cytokine production was accompanied by a 2-fold increase in percentage of iNKT cells expressing the inhibitory marker programmed death-1 in apoE(-/-) mice compared with controls. However, in vivo and in vitro blockade of programmed death-1 using monoclonal antibody was not able to restore functions of iNKT cells from apoE(-/-) mice to B6 levels. iNKT cells from apoE(-/-) mice also had increased intracellular T cell receptor and Ly49 expression, a phenotype associated with previous activation. Changes in iNKT cell functions were cell autonomous, because dendritic cells from apoE(-/-) mice were able to activate B6 iNKT cells, but iNKT cells from apoE(-/-) mice were not able to respond to B6 dendritic cells., Conclusions: These data suggest that chronic dyslipidemia induces an iNKT cell phenotype that is unresponsive to further simulation by exogenous glycolipid and that sustained unresponsiveness is iNKT cell intrinsic.
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- 2010
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11. Apolipoprotein A-I and its role in lymphocyte cholesterol homeostasis and autoimmunity.
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Wilhelm AJ, Zabalawi M, Grayson JM, Weant AE, Major AS, Owen J, Bharadwaj M, Walzem R, Chan L, Oka K, Thomas MJ, and Sorci-Thomas MG
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- Animals, Aorta immunology, Aorta metabolism, Aortic Diseases etiology, Aortic Diseases immunology, Aortic Diseases pathology, Apolipoprotein A-I deficiency, Apolipoprotein A-I genetics, Atherosclerosis etiology, Atherosclerosis immunology, Atherosclerosis pathology, Autoantibodies blood, Cell Proliferation, Cholesterol blood, DNA immunology, Diet, Atherogenic, Disease Models, Animal, Homeostasis, Lipoproteins, LDL immunology, Lymph Nodes immunology, Lymph Nodes metabolism, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, LDL genetics, Receptors, LDL metabolism, Spleen immunology, Spleen metabolism, T-Lymphocytes immunology, Time Factors, beta 2-Glycoprotein I immunology, Aortic Diseases metabolism, Apolipoprotein A-I metabolism, Atherosclerosis metabolism, Autoimmunity, Cholesterol metabolism, T-Lymphocytes metabolism
- Abstract
Objective: The purpose of this study was to determine the effects of an atherogenic diet on immune function in LDLr(-/-), ApoA-I(-/-) mice., Methods and Results: When LDLr(-/-), ApoA-I(-/-) (DKO), and LDLr(-/-) (SKO) mice were fed an atherogenic diet, DKO had larger peripheral lymph nodes (LNs) and spleens compared to SKO mice. LNs were enriched in cholesterol and contain expanded populations of T, B, dendritic cells, and macrophages. Expansion of all classes of LN cells was accompanied by a approximately 1.5-fold increase in T cell proliferation and activation. Plasma antibodies to dsDNA, beta2-glycoprotein I, and oxidized LDL were increased in DKO, similar to levels in diet-fed Fas(lpr/lpr) mice, suggesting the development of an autoimmune phenotype. Both LN enlargement and cellular cholesterol expansion were "prevented" when diet-fed DKO mice were treated with helper dependent adenovirus expressing apoA-I. Independent of the amount of dietary cholesterol, DKO mice consistently showed lower plasma cholesterol than SKO mice, yet greater aortic cholesterol deposition and inflammation., Conclusions: ApoA-I prevented cholesterol-associated lymphocyte activation and proliferation in peripheral LN of diet-fed DKO mice. A approximately 1.5-fold increase in T cell activation and proliferation was associated with a approximately 3-fold increase in concentrations of circulating autoantibodies and approximately 2-fold increase in the severity of atherosclerosis suggesting a common link between plasma apoA-I, inflammation, and atherosclerosis.
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- 2009
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12. Quantitative and qualitative differences in proatherogenic NKT cells in apolipoprotein E-deficient mice.
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Major AS, Wilson MT, McCaleb JL, Ru Su Y, Stanic AK, Joyce S, Van Kaer L, Fazio S, and Linton MF
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- Age Factors, Animals, Antigens, CD1 metabolism, Antigens, CD1 physiology, Aorta chemistry, Aorta metabolism, Aorta pathology, Apolipoproteins E physiology, Cytokines biosynthesis, Galactosylceramides pharmacology, Killer Cells, Natural chemistry, Killer Cells, Natural metabolism, Lymphocyte Activation drug effects, Lymphocyte Activation physiology, Lymphocyte Subsets chemistry, Lymphocyte Subsets metabolism, Lymphocyte Subsets physiology, Male, Mice, Mice, Inbred C57BL, Phenotype, Qualitative Research, Apolipoproteins E deficiency, Arteriosclerosis pathology, Killer Cells, Natural physiology
- Abstract
Background: Atherosclerosis is a disease marked by lipid accumulation and inflammation. Recently, atherosclerosis has gained recognition as an autoimmune-type syndrome characterized by increased activation of the innate and acquired immune systems. Natural killer T (NKT) cells have characteristics of both conventional T cells and NK cells and recognize glycolipid antigens presented in association with CD1d molecules on antigen-presenting cells. The capacity of NKT cells to respond to lipid antigens and modulate innate and acquired immunity suggests that they may play a role in atherogenesis., Methods and Results: We examined the role of NKT cells in atherogenesis and how the atherosclerotic environment affects the NKT cell population itself. The data show that CD1d-deficiency in male apolipoprotein E-deficient (apoE(0)) mice results in reduction in atherosclerosis, and treatment of apoE(0) mice with alpha-galactosylceramide, a potent and specific NKT cell activator, results in a 2-fold increase in atherosclerosis. Interestingly, we demonstrate that alpha-galactosylceramide-induced interferon-gamma responses and numbers of NKT cells in apoE(0) mice show age-dependent qualitative and quantitative differences as compared with age-matched wild-type mice., Conclusions: Collectively, these findings reveal that hyperlipidemia and atherosclerosis have significant effects on NKT cell responses and that these cells are proatherogenic.
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- 2004
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13. Proatherogenic role for NK cells revealed.
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Linton MF, Major AS, and Fazio S
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- Animals, Antigens, Ly genetics, Antigens, Ly physiology, Arteriosclerosis etiology, Genes, Synthetic, Granzymes, Humans, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes genetics, Killer Cells, Natural immunology, Lectins, C-Type, Macrophages physiology, Mice, Mice, Transgenic, Models, Animal, Promoter Regions, Genetic, Receptors, NK Cell Lectin-Like, Serine Endopeptidases genetics, T-Lymphocyte Subsets pathology, Arteriosclerosis immunology, Killer Cells, Natural physiology
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- 2004
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14. B-lymphocyte deficiency increases atherosclerosis in LDL receptor-null mice.
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Major AS, Fazio S, and Linton MF
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- Animals, Antibodies metabolism, Aorta pathology, Arteriosclerosis blood, Arteriosclerosis pathology, Cell Division physiology, Cholesterol blood, Cytokines metabolism, Female, Lipoproteins, LDL immunology, Lymphopenia blood, Lymphopenia complications, Mice, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Mutant Strains, RNA, Messenger metabolism, Spleen chemistry, Spleen cytology, Triglycerides blood, Arteriosclerosis etiology, B-Lymphocytes immunology, B-Lymphocytes pathology, Lymphopenia pathology, Receptors, LDL deficiency, Receptors, LDL genetics
- Abstract
Objective: Atherosclerosis is an inflammatory disease characterized by innate and adaptive immune responses. We investigated the role of B cells and antibodies in the development of atherosclerosis in low density lipoprotein (LDL) receptor-deficient (LDLR(-/-)) mice., Methods and Results: Using wild-type and B cell-deficient mice as bone marrow donors, we were able to generate LDLR(-/-) mice that possessed <1.0% of their normal B cell population. B cell-deficient LDLR(-/-) mice on a Western diet showed marked decreases in total serum antibody and anti-oxidized LDL antibody. B cell deficiency was associated with a 30% to 40% increase in the lesion area in the proximal and distal aortas. Real-time reverse transcription-polymerase chain reaction and enzyme-linked immunospot analyses showed a decrease in proatherogenic (interferon-gamma) and antiatherogenic (interleukin-10 and transforming growth factor-beta) cytokine mRNA and a decrease in interleukin-4- and interferon-gamma-producing cells. Additionally, we observed a decrease in splenocyte proliferation to oxidized LDL in the B cell-deficient LDLR(-/-) mice, suggesting that B lymphocytes may play a role in the presentation of lipid antigen., Conclusions: Collectively, these data demonstrate that B cells and/or antibodies are protective against atherosclerosis and that this protection may be conferred by B cell-mediated immune regulation.
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- 2002
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