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  • 1
    Online Resource
    Online Resource
    Lentiviral shRNA silencing of murine bone marrow cell CCR2 leads to persistent knockdown of CCR2 function in vivo
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 4 ( 2005-08-15), p. 1147-1153
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 4 ( 2005-08-15), p. 1147-1153
    Abstract: A major barrier in hematopoietic gene function studies is posed by the laborious and time-consuming generation of knockout mice with an appropriate genetic background. Here we present a novel lentivirus-based strategy for the in situ generation of hematopoietic knockdowns. A short hairpin RNA (shRNA) was designed targeting murine CC-chemokine receptor 2 (CCR2), which was able to specifically blunt CCR2 expression at the mRNA, protein, and functional levels in vitro. Reconstitution of irradiated recipient mice with autologous bone marrow that had been ex vivo transduced with shRNA lentivirus led to persistent down-regulation of CCR2 expression, which translated into a 70% reduction in CCR2-dependent recruitment of macrophages to an inflamed peritoneal cavity without noticeable side effects on related chemokine receptors or general inflammation status. These findings clearly demonstrate the potential of shRNA lentivirus–infected bone marrow transplantation as a rapid and effective method to generate hematopoietic knockdowns for leukocyte gene function studies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2004-12-4839
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 2
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    Online Resource
    Bone Marrow Transplantation in Apolipoprotein E–Deficient Mice : Effect of ApoE Gene Dosage on Serum Lipid Concentrations, (β)VLDL Catabolism, and Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 17, No. 11 ( 1997-11), p. 3117-3126
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 11 ( 1997-11), p. 3117-3126
    Abstract: Abstract Apolipoprotein E (apoE), a high-affinity ligand for lipoprotein receptors, is synthesized by the liver and extrahepatic tissues, including cells of the monocyte/macrophage lineage. Inactivation of the apoE gene in mice leads to a prominent increase in serum cholesterol and triglyceride levels and the development of premature atherosclerosis. In this study, the role of monocyte/macrophage-derived apoE in lipoprotein remnant metabolism and atherogenesis was assessed. The influence of apoE gene dosage on serum lipid concentrations was determined by transplantation of homozygous apoE-deficient (apoE −/− ), heterozygous apoE-deficient (apoE +/− ), and wild-type (apoE +/+ ) bone marrow in homozygous apoE-deficient mice. The concentration of apoE detected in serum was found to be gene dosage dependent, being 3.52±0.30%, 1.87±0.17%, and 0% of normal in transplanted mice receiving either apoE +/+ , apoE +/− , or apoE −/− bone marrow, respectively. These low concentrations of apoE nevertheless dramatically reduced serum cholesterol levels owing to a reduction of VLDL and, to a lesser extent, LDL, while HDL levels were slightly raised. After 4 months on a “Western-type” diet, atherosclerosis was evidently reduced in mice transplanted with apoE +/+ bone marrow, compared with control transplanted mice. To study the mechanism of the lipoprotein changes on bone marrow transplantation, the in vivo turnover of autologous serum (β)VLDL was studied. The serum half-life of (β)VLDL in transplanted mice, compared with control apoE-deficient mice, was shortened mainly as a consequence of an increased recognition and uptake by the liver. Analysis of the relative contribution of the liver parenchymal cells, endothelial cells, and Kupffer cells (liver tissue macrophages) indicated an increased uptake by parenchymal cells, while the relative contribution of Kupffer cells was decreased. In conclusion, macrophage-derived apoE can dose-dependently reduce hypercholesterolemia in apoE-deficient mice owing to increased recognition and uptake of (β)VLDL by parenchymal liver cells, leading to a decreased susceptibility to atherosclerosis.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.17.11.3117
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 1494427-3
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  • 3
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    Online Resource
    Effect of Human Scavenger Receptor Class A Overexpression in Bone Marrow–Derived Cells on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 12 ( 2000-12), p. 2600-2606
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 12 ( 2000-12), p. 2600-2606
    Abstract: Abstract —In the arterial wall, scavenger receptor class A (SRA) is implicated in pathological lipid deposition. In contrast, in the liver, SRA is suggested to remove modified lipoproteins from the circulation, thereby protecting the body from their pathological action. The role of SRA on bone marrow–derived cells in lipid metabolism and atherogenesis was assessed in vivo by transplantation of bone marrow cells overexpressing human SRA (MSR1) to apoE-deficient mice. In vitro studies with peritoneal macrophages from the transplanted mice showed that macrophage scavenger receptor function, as measured by cell association and degradation studies with acetylated LDL, was ≈3-fold increased on overexpression of MSR1 in bone marrow–derived cells as compared with control mice. Despite the increased macrophage scavenger receptor function in vitro, no significant effect of MSR1 overexpression in bone marrow–derived cells on the in vivo atherosclerotic lesion development was found. In addition to arterial wall macrophages, liver sinusoidal Kupffer cells also overexpress MSR1 after bone marrow transplantation, which may scavenge atherogenic particles more efficiently from the blood compartment. Introduction of bone marrow cells overexpressing human MSR1 in apoE-deficient mice induced a significant reduction in serum cholesterol levels of ≈20% ( P 〈 0.001, 2-way ANOVA) as the result of a decrease in VLDL cholesterol. It is suggested that the reduction in VLDL cholesterol levels is due to increased clearance of modified lipoproteins by the overexpressed MSR1 in Kupffer cells of the liver, thereby protecting the arterial wall against the proatherogenic action of modified lipoproteins.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.12.2600
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1494427-3
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  • 4
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    Effect of Macrophage-Derived Mouse ApoE, Human ApoE3-Leiden, and Human ApoE2 (Arg158→Cys) on Cholesterol Levels and Atherosclerosis in ApoE-Deficient Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 1 ( 2000-01), p. 119-127
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 1 ( 2000-01), p. 119-127
    Abstract: Abstract —The effect of monocyte/macrophage-derived wild-type mouse apolipoprotein E (apoE), human apoE3-Leiden, and human apoE2 on serum cholesterol levels and the development of atherosclerosis in apoE-deficient ( apoe–/– ) mice was investigated by using bone marrow transplantation (BMT). At 4 weeks after BMT, murine apoe+/+ bone marrow reduced serum cholesterol levels by 87% in apoe–/– mice, whereas macrophage-derived human apoE3-Leiden and human apoE2 induced a maximal, transient reduction of 35% and 48%, respectively. At 4 months after BMT, atherosclerosis was 23-fold ( P 〈 0.001) reduced in apoe+/+ → apoe–/– mice, whereas no significant reduction in apoE3-Leiden. apoe–/– → apoe–/– and apoE2. apoe–/– → apoe–/– mice could be demonstrated. A highly significant decrease in serum cholesterol levels (78% reduction) and atherosclerosis (21-fold, P 〈 0.001) was found in apoE3-Leiden. apoe–/– animals expressing high levels of apoE in multiple tissues, whereas apoE2 was ineffective even at high concentrations. Furthermore, in contrast to apoE-deficient macrophages, cholesterol efflux from apoE2 or apoE3-Leiden macrophages was not impaired. In conclusion, apoE3-Leiden as well as apoE2 are less effective in reducing cholesterol levels and atherosclerosis in apoe–/– animals, compared with apoe+/+, with apoE2 〈 apoE3-Leiden 〈 apoe+/+ , irrespective of the observed adequate efflux of cholesterol from macrophages expressing apoE2 and apoE3-Leiden, indicating that normalization of cholesterol efflux by macrophages is not accompanied by measurable effects on lesion growth.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.1.119
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1494427-3
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  • 5
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    Online Resource
    Effect of Bone Marrow Transplantation on Lipoprotein Metabolism and Atherosclerosis in LDL Receptor–Knockout Mice
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 17, No. 10 ( 1997-10), p. 1995-2003
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 10 ( 1997-10), p. 1995-2003
    Abstract: Abstract The LDL receptor (LDLR) plays an important role in the removal of LDL and its precursors, the intermediate and very low density lipoproteins, from the blood circulation. The receptor is expressed on various cell types. In this study the relative importance of the LDLR on macrophages for lipoprotein metabolism and atherogenesis was assessed. For this purpose, irradiated LDLR-knockout (−/−) mice were transplanted with bone marrow of normal C57BL/6J mice. DNA analysis showed that the transplanted mice were chimeric. The transplantation resulted in a slight decrease of total serum cholesterol when compared with LDLR−/− mice that were transplanted with LDLR−/− bone marrow. This modest decrease, however, did not reach statistical significance at all time points examined. This decrease can be almost completely attributed to a decrease in LDL cholesterol. The specific lowering of LDL cholesterol could clearly be observed at 4 weeks after transplantation, but the decrease was less at 12 weeks after transplantation. Quantification of atherosclerotic lesions of mice fed a 1% cholesterol diet for 6 months revealed that there were no differences in mean lesion area between mice transplanted with wild-type bone marrow or LDLR−/− bone marrow. We anticipate that in LDLR−/− mice transplanted with wild-type bone marrow, the LDLR is downregulated by the relatively high concentrations of circulating cholesterol. In vitro incubations of peritoneal macrophages with 125 I-LDL indicated that the LDLR of these cells could be downregulated by 25-hydroxycholesterol. Peritoneal macrophages isolated from LDLR−/− mice transplanted with wild-type bone marrow, in contrast to those transplanted with LDLR−/− bone marrow, were able to degrade 125 I-LDL, indicating that the capacity to express functional LDLR was achieved. In conclusion, introduction of the LDLR into LDLR -/- mice via bone marrow transplantation resulted in only a relatively modest decrease of LDL cholesterol that became less pronounced at later time points, possibly due to downregulation of the LDLR. To utilize the LDLR in macrophages for effective cholesterol lowering, either the sterol-regulatory elements have to be “silenced” or a high-expression LDLR construct has to be introduced into macrophages, eg, via transplantation of in vitro transfected hematopoietic stem cells.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.17.10.1995
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Online Resource
    Low Density Lipoprotein Receptor of Macrophages Facilitates Atherosclerotic Lesion Formation in C57Bl/6 Mice
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 8 ( 2000-08), p. 1961-1967
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 8 ( 2000-08), p. 1961-1967
    Abstract: Abstract —Macrophage-derived foam cells play an important role in the initiation and progression of atherosclerosis. To examine the role of the macrophage low density lipoprotein receptor (LDLr) in atherosclerotic lesion formation, bone marrow from LDLr knockout [LDLr(−/−)] mice was transplanted into irradiated wild-type C57Bl/6 [LDLr(+/+)] mice. After 3 months on an atherogenic diet, C57Bl/6 mice, reconstituted with LDLr(−/−) bone marrow, showed a mean lesion area of 34.7×10 3 ±22.4x10 3 μm 2 compared with 100.8×10 3 ±33.0×10 3 μm 2 ( P 〈 0.001) in control C57Bl/6 mice that were transplanted with LDLr(+/+) bone marrow. There were no significant differences in total serum cholesterol, triglyceride levels, and lipoprotein profiles between the 2 groups. Histochemical analysis of macrophage LDLr expression in the atherosclerotic lesions indicated that C57Bl/6 mice, reconstituted with LDLr(+/+) bone marrow, showed extensive staining of the foam cells in the atherosclerotic lesions, whereas mice reconstituted with LDLr(−/−) bone marrow showed only a few LDLr-positive foam cells. In vitro, peritoneal macrophages isolated from wild-type C57Bl/6 mice were, respectively, 4.7- and 10.7-fold more effective in cell association and degradation of atherogenic 125 I-β-very low density lipoprotein than were LDLr(−/−) peritoneal macrophages, establishing that the LDLr on macrophages is important for the interaction of macrophages with β-very low density lipoprotein. It is concluded that the LDLr on macrophages can facilitate the development of atherosclerosis, possibly by mediating the uptake of atherogenic lipoproteins.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.8.1961
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1494427-3
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  • 7
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    Role of Macrophage-Derived Lipoprotein Lipase in Lipoprotein Metabolism and Atherosclerosis
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 9 ( 2000-09)
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 9 ( 2000-09)
    Abstract: Abstract —Lipoprotein lipase (LPL) synthesis by macrophages is upregulated in early atherogenesis, implicating the possible involvement of LPL in plaque formation. However, it is still unclear whether macrophage-derived LPL displays a proatherosclerotic or an antiatherosclerotic role in atherosclerotic lesion development. In this study, the role of macrophage-derived LPL on lipid metabolism and atherosclerosis was assessed in vivo by transplantation of LPL-deficient (LPL−/−) and wild-type (LPL+/+) bone marrow into C57BL/6 mice. Eight weeks after bone marrow transplantation (BMT), serum cholesterol levels in LPL−/−→C57BL/6 mice were reduced by 8% compared with those in LPL+/+→C57BL/6 mice ( P 〈 0.05, n=16), whereas triglycerides were increased by 33% ( P 〈 0.05, n=16). Feeding the mice a high-cholesterol diet increased serum cholesterol levels in LPL−/−→C57BL/6 and LPL+/+→C57BL/6 mice 5-fold and 9-fold, respectively, resulting in a difference of ≈50% ( P 〈 0.01) after 3 months on the diet. No effects on triglyceride levels were observed under these conditions. Furthermore, serum apolipoprotein E levels were reduced by 50% in the LPL−/−→C57BL/6 mice compared with controls under both dietary conditions. After 3 months on a high-cholesterol diet, the atherosclerotic lesion area in LPL−/−→C57BL/6 mice was reduced by 52% compared with controls. It can be concluded that macrophage-derived LPL plays a significant role in the regulation of serum cholesterol, apolipoprotein E, and atherogenesis, suggesting that specific blockade of macrophage LPL production may be beneficial for decreasing atherosclerotic lesion development.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.9.e53
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1494427-3
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