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Apolipoprotein E3

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Paul H A Quax – One of the best experts on this subject based on the ideXlab platform.

  • Local lentiviral short hairpin RNA silencing of CCR2 inhibits vein graft thickening in hypercholesterolemic Apolipoprotein E3-Leiden mice
    Journal of vascular surgery, 2009
    Co-Authors: Daniel Eefting, Abbey Schepers, Ilze Bot, Margreet R. De Vries, J. Hajo Van Bockel, Theo J.c. Van Berkel, Erik A.l. Biessen, Paul H A Quax

    Abstract:

    Objective: Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the effect of local application of lentiviral short hairpin RNA (shRNA) targeted against CCR2. Methods: A venous interposition was placed into the carotid artery of hypercholesterolemic Apolipoprotein E3-Leiden (APOE*3-Leiden) mice to induce vein graft thickening with features of accelerated atherosclerosis. To demonstrate the efficacy of the lentiviral shRNA targeting murine CCR2 (shCCR2) in blocking vein graft disease in vivo, lentiviral shCCR2 or a control lentivirus was used to infect the vein graft locally (n = 8). Results: Vascular CCR2 and MCP-1 messenger RNA expression levels were significantly upregulated during lesion progression in the vein graft. Infection of smooth muscle cells (SMCs) with a lentiviral shRNA targeting shCCR2 completely abolished MCP-1-induced SMC migration and inhibited SMC proliferation in vitro (n = 3 per group). Morphometric analysis of sections of grafts showed a significant 38% reduction in vein graft thickening in the shCCR2-treated mice 4 weeks after surgery (control, 0.42 ± 0.05 mm2; shCCR2, 0.26 ± 0.03 mm2; P = .007). Conclusion: Vascular CCR2 contributes to vein graft disease, and local application of shRNA against CCR2 to the vessel wall prevents vein graft thickening in hypercholesterolemic mice, suggesting that local overexpressing of shRNA using organ-targeted lentiviral gene delivery may be a promising therapeutic tool to improve vein graft disease in bypassed patients. © 2009 Society for Vascular Surgery.

  • inhibition of complement component c3 reduces vein graft atherosclerosis in Apolipoprotein E3 leiden transgenic mice
    Circulation, 2006
    Co-Authors: Abbey Schepers, M R De Vries, C J Van Leuven, Jos M Grimbergen, V. Michael Holers, Mohamed R. Daha, J. Hajo Van Bockel, Paul H A Quax

    Abstract:

    BACKGROUND – Venous bypass grafts may fail because of development of intimal hyperplasia and accelerated atherosclerosis. Inflammation plays a major role in these processes. Complement is an important part of the immune system and participates in the regulation of inflammation. The exact role of complement in the process of accelerated atherosclerosis of vein grafts has not yet been explored, however. METHODS AND RESULTS – To assess the role of complement in the development of vein graft atherosclerosis, a mouse model, in which a venous interposition was placed in the common carotid artery, was used. In this model, vein graft thickening appeared within 4 weeks. The expression of complement components was studied with the use of immunohistochemistry on sections of the thickened vein graft. C1q, C3, C9, and the regulatory proteins CD59 and complement receptor-related gene y could be detected in the lesions 4 weeks after surgery. Quantitative mRNA analysis for C1q, C3, CD59, and complement receptor-related gene y revealed expression of these molecules in the thickened vein graft, whereas C9 did not show local mRNA expression. Furthermore, interference with C3 activation with complement receptor-related gene y-Ig was associated with reduced vein graft thickening, reduced C3 and C9 deposition, and reduced inflammation as assessed by analysis of influx of inflammatory cells, such as leukocytes, T cells, and monocytes. In addition, changes in apoptosis and proliferation were observed. When C3 was inhibited by cobra venom factor, a similar reduction in vein graft thickening was observed. CONCLUSIONS – The complement cascade is involved in vein graft thickening and may be a target for therapy in vein graft failure disease. © 2006 American Heart Association, Inc. Chemicals / CAS: cobrotoxin, 12584-83-7, 8001-03-4; complement component C1q, 80295-33-6; complement component C3, 80295-41-6; Apolipoprotein E3 (Leidein); Apolipoprotein E3; Complement C3

  • Inhibition of Complement Component C3 Reduces Vein Graft Atherosclerosis in Apolipoprotein E3–Leiden Transgenic Mice
    Circulation, 2006
    Co-Authors: Abbey Schepers, M R De Vries, Jos M Grimbergen, V. Michael Holers, Mohamed R. Daha, C.j. Van Leuven, J. H. Van Bockel, Paul H A Quax

    Abstract:

    BACKGROUND – Venous bypass grafts may fail because of development of intimal hyperplasia and accelerated atherosclerosis. Inflammation plays a major role in these processes. Complement is an important part of the immune system and participates in the regulation of inflammation. The exact role of complement in the process of accelerated atherosclerosis of vein grafts has not yet been explored, however. METHODS AND RESULTS – To assess the role of complement in the development of vein graft atherosclerosis, a mouse model, in which a venous interposition was placed in the common carotid artery, was used. In this model, vein graft thickening appeared within 4 weeks. The expression of complement components was studied with the use of immunohistochemistry on sections of the thickened vein graft. C1q, C3, C9, and the regulatory proteins CD59 and complement receptor-related gene y could be detected in the lesions 4 weeks after surgery. Quantitative mRNA analysis for C1q, C3, CD59, and complement receptor-related gene y revealed expression of these molecules in the thickened vein graft, whereas C9 did not show local mRNA expression. Furthermore, interference with C3 activation with complement receptor-related gene y-Ig was associated with reduced vein graft thickening, reduced C3 and C9 deposition, and reduced inflammation as assessed by analysis of influx of inflammatory cells, such as leukocytes, T cells, and monocytes. In addition, changes in apoptosis and proliferation were observed. When C3 was inhibited by cobra venom factor, a similar reduction in vein graft thickening was observed. CONCLUSIONS – The complement cascade is involved in vein graft thickening and may be a target for therapy in vein graft failure disease. © 2006 American Heart Association, Inc. Chemicals / CAS: cobrotoxin, 12584-83-7, 8001-03-4; complement component C1q, 80295-33-6; complement component C3, 80295-41-6; Apolipoprotein E3 (Leidein); Apolipoprotein E3; Complement C3

Vasanthy Narayanaswami – One of the best experts on this subject based on the ideXlab platform.

  • Cellular Uptake and Clearance of Oxidatively-modified Apolipoprotein E3 by Cerebral Cortex Endothelial Cells.
    International journal of molecular sciences, 2019
    Co-Authors: Siobanth Cruz, Vasanthy Narayanaswami

    Abstract:

    Apolipoprotein E3 (apoE3) plays a critical role in the metabolism of lipoproteins and lowers plasma lipid levels by serving as a ligand for the low-density lipoprotein receptor (LDLr) family of proteins and by promoting macrophage cholesterol efflux. The current study examines the effect of acrolein (an endogenously generated metabolite and an environmental pollutant) modification on the structure and function of apoE3. Acrolein modification was confirmed in Western blots by reactivity with acrolein–lysine-specific antibody and by the presence of oligomeric species due to cross-linking. LC-MS/MS analysis revealed modification of 10 out of 12 lysines in apoE3, with Ne-(3-methylpyridinium)-lysine being the predominant form of modification, and Lys75 being a ‘hot spot’ in terms of susceptibility to oxidation. Circular dichroism spectroscopy showed no major change in overall secondary structure compared to unmodified apoE3. Reconstituted high density lipoprotein (HDL) bearing acrolein modified apoE3 showed loss of binding to soluble LDLr; however, incubation with mouse endothelioma bEnd.3 cells showed that it was internalized. Incubation with excess LDL did not abolish cellular uptake of acrolein modified apoE3, suggesting alternative mechanism(s) not involving LDLr. Incubation with anti-CD36 antibody did not show a decrease in internalization while incubation with anti- lectin-like oxidized LDL receptor 1 (LOX1) showed partial internalization. However, incubation with anti-scavenger receptor class B type I (SRB1) antibody abolished internalization of acrolein modified apoE3. Taken together, our studies suggest that acrolein modification of apoE3 at lysine residues leads to increase in net negative charge, and as a consequence, results in clearance by LOX1 and SRB1 on endothelial cells. Overall, oxidative modification of apoE3 likely impairs its role in regulating plasma cholesterol homeostasis, eventually leading to lipid disorders.

  • conformational analysis of Apolipoprotein E3 e4 heteromerization
    FEBS Journal, 2019
    Co-Authors: Devan Abhari, Vasanthy Narayanaswami

    Abstract:

    Apolipoprotein E (apoE) is a 299 residue, exchangeable Apolipoprotein that has essential roles in cholesterol homeostasis and reverse cholesterol transport. It is a two-domain protein with the C-terminal (CT) domain mediating protein self-association via helix-helix interactions. In humans, the APOE gene is polymorphic with three common alleles, e2, E3, and e4, occurring in frequencies of ~ 5%, 77%, and 18%, respectively. Heterozygotes expressing apoE3 and apoE4 isoforms, which differ in residue at position 112 in the N-terminal domain (C112 in apoE3 and R112 in apoE4), represent the highest population of e4 carriers, an allele highly associated with Alzheimer’s disease. The objective of this study was to determine if apoE3 and apoE4 have the ability to hybridize to form a heteromer in lipid-free state. Refolding an equimolar mixture of His-apoE3 and FLAG-apoE4 (or vice versa) followed by pull-down and immunoblotting indicated formation of apoE3/apoE4 heteromers. Forster resonance energy transfer between donor fluorophore on one isoform and acceptor on the other, both located in the respective CT domains, revealed a distance of separation of ~ 46 A between the donor/acceptor pair. Similarly, a quencher placed on one was able to mediate significant quenching of fluorescence emission on the other, indicative of spatial proximity within collisional distance between the two. ApoE3/apoE4 heteromer association was also noted in lipid-associated state in reconstituted lipoprotein particles. The possibility of heteromerization of apoE3/apoE4 bears implications in the potential mitigating role of apoE3 on the folding and physiological behavior of apoE4 and its role in maintaining cholesterol homeostasis.

  • Conformational analysis of Apolipoprotein E3/E4 heteromerization.
    The FEBS journal, 2019
    Co-Authors: Devan Abhari, Vasanthy Narayanaswami

    Abstract:

    Apolipoprotein E (apoE) is a 299 residue, exchangeable Apolipoprotein that has essential roles in cholesterol homeostasis and reverse cholesterol transport. It is a two-domain protein with the C-terminal (CT) domain mediating protein self-association via helix-helix interactions. In humans, the APOE gene is polymorphic with three common alleles, e2, E3, and e4, occurring in frequencies of ~ 5%, 77%, and 18%, respectively. Heterozygotes expressing apoE3 and apoE4 isoforms, which differ in residue at position 112 in the N-terminal domain (C112 in apoE3 and R112 in apoE4), represent the highest population of e4 carriers, an allele highly associated with Alzheimer’s disease. The objective of this study was to determine if apoE3 and apoE4 have the ability to hybridize to form a heteromer in lipid-free state. Refolding an equimolar mixture of His-apoE3 and FLAG-apoE4 (or vice versa) followed by pull-down and immunoblotting indicated formation of apoE3/apoE4 heteromers. Forster resonance energy transfer between donor fluorophore on one isoform and acceptor on the other, both located in the respective CT domains, revealed a distance of separation of ~ 46 A between the donor/acceptor pair. Similarly, a quencher placed on one was able to mediate significant quenching of fluorescence emission on the other, indicative of spatial proximity within collisional distance between the two. ApoE3/apoE4 heteromer association was also noted in lipid-associated state in reconstituted lipoprotein particles. The possibility of heteromerization of apoE3/apoE4 bears implications in the potential mitigating role of apoE3 on the folding and physiological behavior of apoE4 and its role in maintaining cholesterol homeostasis.

Gang Zheng – One of the best experts on this subject based on the ideXlab platform.

  • Correction: Tailored theranostic Apolipoprotein E3 porphyrin-lipid nanoparticles target glioblastoma.
    Chemical science, 2017
    Co-Authors: Maneesha A. Rajora, Lili Ding, Michael S. Valic, Wenlei Jiang, Marta Overchuk, Juan Chen, Gang Zheng

    Abstract:

    Correction for ‘Tailored theranostic Apolipoprotein E3 porphyrin-lipid nanoparticles target glioblastoma’ by M. A. Rajora et al., Chem. Sci., 2017, DOI: 10.1039/c7sc00732a.

  • Tailored theranostic Apolipoprotein E3 porphyrin-lipid nanoparticles target glioblastoma
    Chemical science, 2017
    Co-Authors: Maneesha A. Rajora, Lili Ding, Michael S. Valic, Wenlei Jiang, Marta Overchuk, Juan Chen, Gang Zheng

    Abstract:

    The development of curative glioblastoma treatments and tumour-specific contrast agents that can overcome the blood–brain barrier (BBB) and infiltrative tumour morphology remains a challenge. Apolipoprotein E3 (apoE3) is a high density lipoprotein Apolipoprotein that chaperones the transcytosis of nanoparticles across the BBB, and displays high-affinity binding with the low density lipoprotein receptor (LDLR), a cell-surface receptor overexpressed by glioblastoma cells. This LDLR overexpression and apoE3 binding capacity was exploited for the development of glioblastoma-targeted porphyrin-lipid apoE3 lipid nanoparticles (pyE-LNs) with intrinsic theranostic properties. Size-controlled discoidal and cholesteryl oleate (CO)-loaded spherical pyE-LNs were synthesized through the systematic variation of particle composition, which dictated nanoparticle size and morphology. Composition optimization yielded 30 nm pyE-LNs with stable loading of apoE3 and porphyrin-lipid that simultaneously conferred the nanoparticles with glioblastoma targeting and activatable near-infrared fluorescence imaging functionalities. A 4-fold higher uptake of pyE-LNs by LDLR-expressing U87 glioblastomas cells relative to minimally expressing ldlA7 cells was observed in vitro. This uptake was a result of receptor-mediated endocytosis, which could be inhibited through LDL competition and acetylation of particle apoE3 moieties. ApoE3-dependent delivery of pyE-LN to glioblastomas was also demonstrated in orthotopic U87-GFP tumour-bearing animals. Quantification of CO-loaded pyE-LN biodistribution demonstrated successful selective uptake of porphyrin by malignant tissue, with a 4 : 1 tumour : healthy tissue particle specificity. This allowed for the detection of strong, tumour-localized porphyrin fluorescence, which was diminished when apoE3-devoid py-LN particles were administered. Furthermore, this selective uptake yielded cell-specific potent PDT sensitization in vitro, resulting in an 83% reduction in glioblastoma cell viability. These results highlight the promising capacity of pyE-LNs to target porphyrin delivery to glioblastoma tumours for theranostic applications.