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Miranda Van Eck - One of the best experts on this subject based on the ideXlab platform.
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Independent protective roles for macrophage Abcg1 and Apoe in the atherosclerotic Lesion Development.
Atherosclerosis, 2009Co-Authors: Bart Lammers, Menno Hoekstra, Reeni B. Hildebrand, Theo J.c. Van Berkel, Ruud Out, Illiana Meurs, Carmel M. Quinn, David Williamson, Wendy Jessup, Miranda Van EckAbstract:Abstract Objective ATP-binding cassette transporter G1 (Abcg1) and apolipoprotein E (Apoe) play a role in macrophage cholesterol efflux and consequently the Development of atherosclerosis. A possible interaction between Abcg1 and Apoe in cholesterol efflux was postulated, but the potential combined action of these proteins on atherosclerotic Lesion formation is unclear. Methods LDL receptor knockout (KO) mice were transplanted with bone marrow from Abcg1/Apoe double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls and challenged with a high-fat/high-cholesterol diet for 6 weeks to induce atherosclerosis. Results No differences were found in serum lipid levels. The mean atherosclerotic Lesion area in dKO transplanted animals (187±18×10 3 μm 2 ) was 1.4-fold ( p 3 μm 2 ; Apoe KO: 131±7×10 3 μm 2 ) and 1.9-fold ( p 3 μm 2 ). In vitro cholesterol efflux experiments established that combined deletion of Abcg1 and Apoe leads to a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Single deletion of macrophage Abcg1 or Apoe does lead to a moderate non-significant increase in atherosclerotic Lesion Development as tested by ANOVA, while combined deletion of Abcg1 and Apoe induces a more dramatic and significant increase in atherosclerosis. Our results indicate an additive, independent effect for both macrophage Abcg1 and Apoe in the prevention of atherosclerosis.
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Bone marrow-derived multidrug resistance protein ABCB4 protects against atherosclerotic Lesion Development in LDL receptor knockout mice
Cardiovascular Research, 2007Co-Authors: Marieke Pennings, Reeni B. Hildebrand, Theo J.c. Van Berkel, Cindy Kunne, Albert K. Groen, Miranda Van EckAbstract:Objective Several members of the ATP binding cassette (ABC)-transporter super family expressed in macrophages protect against atherosclerosis by promoting macrophage cholesterol and phospholipid efflux. Systemic disruption of ABCB4 in mice results in a virtual absence of phospholipids in bile and a strongly impaired biliary cholesterol secretion, indicating that ABCB4 plays an essential role in cellular lipid efflux. The aim of the current study was to determine the role of bone marrow-derived ABCB4 in atherosclerotic Lesion Development. Methods Chimeras were created that specifically lack ABCB4 in bone marrow-derived cells, including macrophages, by performing a bone marrow transplantation on LDL receptor knockout (LDLr−/−) mice. Atherosclerotic Lesion Development was induced by feeding a high-cholesterol diet (15% fat and 0.25% cholesterol). Results Serum cholesterol levels were significantly lower in mice reconstituted with ABCB4 knockout bone marrow as a result of reduced VLDL and LDL cholesterol levels. Despite the lower serum cholesterol levels, ABCB4 deficiency in bone marrow-derived cells resulted in a 1.8-fold ( p =0.005) increase in Lesion size. In vitro foam cell formation, induced with acetylated LDL (AcLDL) in peritoneal macrophages, was increased in the absence of ABCB4, possibly due to a 2-fold ( p
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macrophage phospholipid transfer protein contributes significantly to total plasma phospholipid transfer activity and its deficiency leads to diminished atherosclerotic Lesion Development
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Riikka Vikstedt, Reeni B. Hildebrand, Theo J.c. Van Berkel, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Miranda Van EckAbstract:Objective— Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic Lesion Development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic Lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P <0.01 for difference in Lesion area) reduction in aortic root Lesion area as compared with mice possessing functional macrophage PLTP (384±36*103 μm2 in the PLTP−M/−M group (n=10), as compared with 539±35*103 μm2 in the PLTP+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased Lesion size in the PLTP−M/−M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP−M/−M group was 2-fold ( P <0.001) lower than that in the PLTP+M/+M group. Conclusion— Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic Lesion Development in low-density lipoprotein receptor knockout mice on Western-type diet.
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Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Ruud Out, Miranda Van Eck, Menno Hoekstra, Illiana Meurs, Paula De Vos, Johan Kuiper, Theo J.c. Van BerkelAbstract:Objective— ABCG1 has recently been identified as a facilitator of cholesterol and phospholipid efflux from macrophages to HDL. In bone marrow transplantation studies, we and others have now shown that the absence of macrophage ABCG1 may differentially influence atherosclerotic Lesions dependent on the experimental setting and/or the stage of atherosclerotic Lesion Development. To further define the role of ABCG1 in atherogenesis, we investigated in the current study the effect of total body deficiency of ABCG1 on atherosclerotic Lesion Development. Methods and Results— ABCG1 −/− mice and wild-type littermates were fed an atherogenic diet for 12 weeks to induce atherosclerotic Lesion formation. Both before and after the start of the atherogenic diet, serum lipid levels and lipoprotein profiles did not differ significantly between the two groups. In addition no significant difference in serum apoE levels was found after diet feeding. In wild-type mice the atherogenic diet induced the formation of macrophage-rich early Lesions (size: 24±7×10 3 μm 2 [n=6]). Feeding ABCG1 −/− mice the atherogenic diet led to a significant 1.9-fold stimulation of atherosclerotic Lesion size (46±6x10 3 μm 2 [n=7]; Student t test P =0.034 and Mann–Whitney test P =0.050) compared with controls, suggesting a clear antiatherogenic role for ABCG1. At the same time, excessive lipid accumulation was observed in macrophage-rich areas of the lungs and spleens of ABCG1 −/− mice as compared with wild-type mice. Conclusions— Total body ABCG1 expression protects against early atherosclerotic Lesion Development.
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Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Riikka Vikstedt, Reeni B. Hildebrand, Theo J.c. Van Berkel, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Miranda Van EckAbstract:Objective— Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic Lesion Development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic Lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P
Maria Febbraio - One of the best experts on this subject based on the ideXlab platform.
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continued inhibition of atherosclerotic Lesion Development in long term western diet fed cd36 apoe mice
Atherosclerosis, 2007Co-Authors: Ella Guy, Sai Kuchibhotla, Roy L. Silverstein, Maria FebbraioAbstract:We previously determined that absence of CD36 inhibited atherosclerosis Lesion Development in 12-week Western diet fed apoE° mice, and this was due largely to absence of macrophage CD36. It is possible that at later stages of disease this effect would be lost due to the progressive nature of Lesion Development and involvement of other factors. However, Lesion Development continues to be characterized by recruitment of macrophages and foam cell formation, thus it is also possible that delay in lipid accumulation as a result of absence of CD36 would continue to retard Lesion Development. The objective of this study was to determine if absence of CD36 continued to inhibit Lesion formation. Background matched apoE° and CD36°/apoE° mice were fed a Western diet for up to 35 weeks. At 20 and 35 weeks, Lesion area was 25 and 35% less, respectively, in CD36°/apoE° mice. Most impressive was the difference in gross appearance of the aortas at 35 weeks: apoE° aortas were sclerotic and nearly occluded by Lesion, whereas aortas from CD36°/apoE° mice had smaller Lesions that were more punctate. We conclude that absence of CD36 continues to reduce Lesion burden even at late stages of disease in the apoE° model.
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Continued inhibition of atherosclerotic Lesion Development in long term Western diet fed CD36°/apoE° mice
Atherosclerosis, 2006Co-Authors: Ella Guy, Sai Kuchibhotla, Roy L. Silverstein, Maria FebbraioAbstract:We previously determined that absence of CD36 inhibited atherosclerosis Lesion Development in 12-week Western diet fed apoE° mice, and this was due largely to absence of macrophage CD36. It is possible that at later stages of disease this effect would be lost due to the progressive nature of Lesion Development and involvement of other factors. However, Lesion Development continues to be characterized by recruitment of macrophages and foam cell formation, thus it is also possible that delay in lipid accumulation as a result of absence of CD36 would continue to retard Lesion Development. The objective of this study was to determine if absence of CD36 continued to inhibit Lesion formation. Background matched apoE° and CD36°/apoE° mice were fed a Western diet for up to 35 weeks. At 20 and 35 weeks, Lesion area was 25 and 35% less, respectively, in CD36°/apoE° mice. Most impressive was the difference in gross appearance of the aortas at 35 weeks: apoE° aortas were sclerotic and nearly occluded by Lesion, whereas aortas from CD36°/apoE° mice had smaller Lesions that were more punctate. We conclude that absence of CD36 continues to reduce Lesion burden even at late stages of disease in the apoE° model.
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targeted disruption of the class b scavenger receptor cd36 protects against atherosclerotic Lesion Development in mice
Journal of Clinical Investigation, 2000Co-Authors: Maria Febbraio, Eugene A Podrez, Jonathan D Smith, David P Hajjar, Stanley L Hazen, Henry F Hoff, Kavita Sharma, Roy L. SilversteinAbstract:Macrophage scavenger receptors have been implicated as key players in the pathogenesis of atherosclerosis. To assess the role of the class B scavenger receptor CD36 in atherogenesis, we crossed a CD36-null strain with the atherogenic apo E–null strain and quantified Lesion Development. There was a 76.5% decrease in aortic tree Lesion area (Western diet) and a 45% decrease in aortic sinus Lesion area (normal chow) in the CD36-apo E double-null mice when compared with controls, despite alterations in lipoprotein profiles that often correlate with increased atherogenicity. Macrophages derived from CD36-apo E double-null mice bound and internalized more than 60% less copper-oxidized LDL and LDL modified by monocyte-generated reactive nitrogen species. A similar inhibition of in vitro lipid accumulation and foam cell formation after exposure to these ligands was seen. These results support a major role for CD36 in atherosclerotic Lesion Development in vivo and suggest that blockade of CD36 can be protective even in more extreme proatherogenic circumstances.
Roy L. Silverstein - One of the best experts on this subject based on the ideXlab platform.
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Vav Guanine Nucleotide Exchange Factors Regulate Atherosclerotic Lesion Development in Mice
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: O. Rahaman, Roy L. SilversteinAbstract:Objective—Atherosclerosis requires migration of monocytes to the arterial intima, with subsequent differentiation into foam cells. We showed previously that the scavenger receptor CD36 contributes to the activation of Vav family guanine nucleotide exchange factors (Vavs) in aortae from hyperlipidemic apoE-null mice and that oxidatively modified low-density lipoprotein induced CD36-dependent activation of macrophage Vavs in vitro. We also discovered that CD36-dependent uptake of oxidized low-density lipoprotein and foam cell formation were reduced in Vav-deficient macrophages. We now tested the hypothesis that Vavs play a role in atherosclerotic Lesion Development. Approach and Results—We showed that apoE/vav1 double-null mice fed a Western diet had significant reduction in total aortic Lesion area (by en face analysis) compared with apoE-null mice, with no significant differences in body weight or plasma lipid profiles. Histological analysis of aortic sinus Lesions showed fewer macrophages and foam cells ...
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continued inhibition of atherosclerotic Lesion Development in long term western diet fed cd36 apoe mice
Atherosclerosis, 2007Co-Authors: Ella Guy, Sai Kuchibhotla, Roy L. Silverstein, Maria FebbraioAbstract:We previously determined that absence of CD36 inhibited atherosclerosis Lesion Development in 12-week Western diet fed apoE° mice, and this was due largely to absence of macrophage CD36. It is possible that at later stages of disease this effect would be lost due to the progressive nature of Lesion Development and involvement of other factors. However, Lesion Development continues to be characterized by recruitment of macrophages and foam cell formation, thus it is also possible that delay in lipid accumulation as a result of absence of CD36 would continue to retard Lesion Development. The objective of this study was to determine if absence of CD36 continued to inhibit Lesion formation. Background matched apoE° and CD36°/apoE° mice were fed a Western diet for up to 35 weeks. At 20 and 35 weeks, Lesion area was 25 and 35% less, respectively, in CD36°/apoE° mice. Most impressive was the difference in gross appearance of the aortas at 35 weeks: apoE° aortas were sclerotic and nearly occluded by Lesion, whereas aortas from CD36°/apoE° mice had smaller Lesions that were more punctate. We conclude that absence of CD36 continues to reduce Lesion burden even at late stages of disease in the apoE° model.
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Continued inhibition of atherosclerotic Lesion Development in long term Western diet fed CD36°/apoE° mice
Atherosclerosis, 2006Co-Authors: Ella Guy, Sai Kuchibhotla, Roy L. Silverstein, Maria FebbraioAbstract:We previously determined that absence of CD36 inhibited atherosclerosis Lesion Development in 12-week Western diet fed apoE° mice, and this was due largely to absence of macrophage CD36. It is possible that at later stages of disease this effect would be lost due to the progressive nature of Lesion Development and involvement of other factors. However, Lesion Development continues to be characterized by recruitment of macrophages and foam cell formation, thus it is also possible that delay in lipid accumulation as a result of absence of CD36 would continue to retard Lesion Development. The objective of this study was to determine if absence of CD36 continued to inhibit Lesion formation. Background matched apoE° and CD36°/apoE° mice were fed a Western diet for up to 35 weeks. At 20 and 35 weeks, Lesion area was 25 and 35% less, respectively, in CD36°/apoE° mice. Most impressive was the difference in gross appearance of the aortas at 35 weeks: apoE° aortas were sclerotic and nearly occluded by Lesion, whereas aortas from CD36°/apoE° mice had smaller Lesions that were more punctate. We conclude that absence of CD36 continues to reduce Lesion burden even at late stages of disease in the apoE° model.
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targeted disruption of the class b scavenger receptor cd36 protects against atherosclerotic Lesion Development in mice
Journal of Clinical Investigation, 2000Co-Authors: Maria Febbraio, Eugene A Podrez, Jonathan D Smith, David P Hajjar, Stanley L Hazen, Henry F Hoff, Kavita Sharma, Roy L. SilversteinAbstract:Macrophage scavenger receptors have been implicated as key players in the pathogenesis of atherosclerosis. To assess the role of the class B scavenger receptor CD36 in atherogenesis, we crossed a CD36-null strain with the atherogenic apo E–null strain and quantified Lesion Development. There was a 76.5% decrease in aortic tree Lesion area (Western diet) and a 45% decrease in aortic sinus Lesion area (normal chow) in the CD36-apo E double-null mice when compared with controls, despite alterations in lipoprotein profiles that often correlate with increased atherogenicity. Macrophages derived from CD36-apo E double-null mice bound and internalized more than 60% less copper-oxidized LDL and LDL modified by monocyte-generated reactive nitrogen species. A similar inhibition of in vitro lipid accumulation and foam cell formation after exposure to these ligands was seen. These results support a major role for CD36 in atherosclerotic Lesion Development in vivo and suggest that blockade of CD36 can be protective even in more extreme proatherogenic circumstances.
Jon C Aster - One of the best experts on this subject based on the ideXlab platform.
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macrophage notch ligand delta like 4 promotes vein graft Lesion Development implications for the treatment of vein graft failure
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Junichiro Koga, James E Dahlman, Tomiharu Niida, Hiroshi Iwata, Joseluiz Figueiredo, Toshiaki Nakano, Hengmin Zhang, Julius L. Decano, Omar F. Khan, Jon C AsterAbstract:Objective— Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results— We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage- or endothelial cell (EC)–targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft Lesion Development in low-density lipoprotein (LDL) receptor-deficient ( Ldlr −/− ) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced Lesion Development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that Dll4 induces proinflammatory molecules in macrophages. Macrophage Dll4 also stimulated smooth muscle cell proliferation and migration and suppressed their differentiation. Conclusions— These results suggest that macrophage Dll4 promotes Lesion Development in vein grafts via macrophage activation and crosstalk between macrophages and smooth muscle cells, supporting the Dll4–Notch axis as a novel therapeutic target.
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macrophage notch ligand delta like 4 promotes vein graft Lesion Development implications for the treatment of vein graft failure
Arteriosclerosis Thrombosis and Vascular Biology, 2015Co-Authors: Junichiro Koga, James E Dahlman, Tomiharu Niida, Hiroshi Iwata, Joseluiz Figueiredo, Toshiaki Nakano, Hengmin Zhang, Julius L. Decano, Omar F. Khan, Jon C AsterAbstract:Objective—Despite its large clinical impact, the underlying mechanisms for vein graft failure remain obscure and no effective therapeutic solutions are available. We tested the hypothesis that Notch signaling promotes vein graft disease. Approach and Results—We used 2 biotherapeutics for Delta-like ligand 4 (Dll4), a Notch ligand: (1) blocking antibody and (2) macrophage- or endothelial cell (EC)–targeted small-interfering RNA. Dll4 antibody administration for 28 days inhibited vein graft Lesion Development in low-density lipoprotein (LDL) receptor-deficient (Ldlr−/−) mice, and suppressed macrophage accumulation and macrophage expression of proinflammatory M1 genes. Dll4 antibody treatment for 7 days after grafting also reduced macrophage burden at day 28. Dll4 silencing via macrophage-targeted lipid nanoparticles reduced Lesion Development and macrophage accumulation, whereas EC-targeted Dll4 small-interfering RNA produced no effects. Gain-of-function and loss-of-function studies suggested in vitro that ...
Theo J.c. Van Berkel - One of the best experts on this subject based on the ideXlab platform.
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Independent protective roles for macrophage Abcg1 and Apoe in the atherosclerotic Lesion Development.
Atherosclerosis, 2009Co-Authors: Bart Lammers, Menno Hoekstra, Reeni B. Hildebrand, Theo J.c. Van Berkel, Ruud Out, Illiana Meurs, Carmel M. Quinn, David Williamson, Wendy Jessup, Miranda Van EckAbstract:Abstract Objective ATP-binding cassette transporter G1 (Abcg1) and apolipoprotein E (Apoe) play a role in macrophage cholesterol efflux and consequently the Development of atherosclerosis. A possible interaction between Abcg1 and Apoe in cholesterol efflux was postulated, but the potential combined action of these proteins on atherosclerotic Lesion formation is unclear. Methods LDL receptor knockout (KO) mice were transplanted with bone marrow from Abcg1/Apoe double KO (dKO) mice, their respective single knockouts, and wild-type (WT) controls and challenged with a high-fat/high-cholesterol diet for 6 weeks to induce atherosclerosis. Results No differences were found in serum lipid levels. The mean atherosclerotic Lesion area in dKO transplanted animals (187±18×10 3 μm 2 ) was 1.4-fold ( p 3 μm 2 ; Apoe KO: 131±7×10 3 μm 2 ) and 1.9-fold ( p 3 μm 2 ). In vitro cholesterol efflux experiments established that combined deletion of Abcg1 and Apoe leads to a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Single deletion of macrophage Abcg1 or Apoe does lead to a moderate non-significant increase in atherosclerotic Lesion Development as tested by ANOVA, while combined deletion of Abcg1 and Apoe induces a more dramatic and significant increase in atherosclerosis. Our results indicate an additive, independent effect for both macrophage Abcg1 and Apoe in the prevention of atherosclerosis.
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Bone marrow-derived multidrug resistance protein ABCB4 protects against atherosclerotic Lesion Development in LDL receptor knockout mice
Cardiovascular Research, 2007Co-Authors: Marieke Pennings, Reeni B. Hildebrand, Theo J.c. Van Berkel, Cindy Kunne, Albert K. Groen, Miranda Van EckAbstract:Objective Several members of the ATP binding cassette (ABC)-transporter super family expressed in macrophages protect against atherosclerosis by promoting macrophage cholesterol and phospholipid efflux. Systemic disruption of ABCB4 in mice results in a virtual absence of phospholipids in bile and a strongly impaired biliary cholesterol secretion, indicating that ABCB4 plays an essential role in cellular lipid efflux. The aim of the current study was to determine the role of bone marrow-derived ABCB4 in atherosclerotic Lesion Development. Methods Chimeras were created that specifically lack ABCB4 in bone marrow-derived cells, including macrophages, by performing a bone marrow transplantation on LDL receptor knockout (LDLr−/−) mice. Atherosclerotic Lesion Development was induced by feeding a high-cholesterol diet (15% fat and 0.25% cholesterol). Results Serum cholesterol levels were significantly lower in mice reconstituted with ABCB4 knockout bone marrow as a result of reduced VLDL and LDL cholesterol levels. Despite the lower serum cholesterol levels, ABCB4 deficiency in bone marrow-derived cells resulted in a 1.8-fold ( p =0.005) increase in Lesion size. In vitro foam cell formation, induced with acetylated LDL (AcLDL) in peritoneal macrophages, was increased in the absence of ABCB4, possibly due to a 2-fold ( p
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macrophage phospholipid transfer protein contributes significantly to total plasma phospholipid transfer activity and its deficiency leads to diminished atherosclerotic Lesion Development
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Riikka Vikstedt, Reeni B. Hildebrand, Theo J.c. Van Berkel, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Miranda Van EckAbstract:Objective— Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic Lesion Development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic Lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P <0.01 for difference in Lesion area) reduction in aortic root Lesion area as compared with mice possessing functional macrophage PLTP (384±36*103 μm2 in the PLTP−M/−M group (n=10), as compared with 539±35*103 μm2 in the PLTP+M/+M group (n=14)) after 9 weeks of Western-type diet feeding. The decreased Lesion size in the PLTP−M/−M group coincided with significantly lower serum total cholesterol, free cholesterol, and triglyceride levels in these mice. Furthermore, plasma PLTP activity in the PLTP−M/−M group was 2-fold ( P <0.001) lower than that in the PLTP+M/+M group. Conclusion— Macrophage PLTP is a significant contributor to plasma PLTP activity and deficiency of PLTP in macrophages leads to lowered atherosclerotic Lesion Development in low-density lipoprotein receptor knockout mice on Western-type diet.
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Total Body ABCG1 Expression Protects Against Early Atherosclerotic Lesion Development in Mice
Arteriosclerosis Thrombosis and Vascular Biology, 2007Co-Authors: Ruud Out, Miranda Van Eck, Menno Hoekstra, Illiana Meurs, Paula De Vos, Johan Kuiper, Theo J.c. Van BerkelAbstract:Objective— ABCG1 has recently been identified as a facilitator of cholesterol and phospholipid efflux from macrophages to HDL. In bone marrow transplantation studies, we and others have now shown that the absence of macrophage ABCG1 may differentially influence atherosclerotic Lesions dependent on the experimental setting and/or the stage of atherosclerotic Lesion Development. To further define the role of ABCG1 in atherogenesis, we investigated in the current study the effect of total body deficiency of ABCG1 on atherosclerotic Lesion Development. Methods and Results— ABCG1 −/− mice and wild-type littermates were fed an atherogenic diet for 12 weeks to induce atherosclerotic Lesion formation. Both before and after the start of the atherogenic diet, serum lipid levels and lipoprotein profiles did not differ significantly between the two groups. In addition no significant difference in serum apoE levels was found after diet feeding. In wild-type mice the atherogenic diet induced the formation of macrophage-rich early Lesions (size: 24±7×10 3 μm 2 [n=6]). Feeding ABCG1 −/− mice the atherogenic diet led to a significant 1.9-fold stimulation of atherosclerotic Lesion size (46±6x10 3 μm 2 [n=7]; Student t test P =0.034 and Mann–Whitney test P =0.050) compared with controls, suggesting a clear antiatherogenic role for ABCG1. At the same time, excessive lipid accumulation was observed in macrophage-rich areas of the lungs and spleens of ABCG1 −/− mice as compared with wild-type mice. Conclusions— Total body ABCG1 expression protects against early atherosclerotic Lesion Development.
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Macrophage Phospholipid Transfer Protein Contributes Significantly to Total Plasma Phospholipid Transfer Activity and Its Deficiency Leads to Diminished Atherosclerotic Lesion Development
Arteriosclerosis Thrombosis and Vascular Biology, 2006Co-Authors: Riikka Vikstedt, Reeni B. Hildebrand, Theo J.c. Van Berkel, Jari Metso, Christian Ehnholm, Matti Jauhiainen, Miranda Van EckAbstract:Objective— Systemic phospholipid transfer protein (PLTP) deficiency in mice is associated with a decreased susceptibility to atherosclerosis, whereas overexpression of human PLTP in mice increases atherosclerotic Lesion Development. PLTP is also expressed by macrophage-derived foam cells in human atherosclerotic Lesions, but the exact role of macrophage PLTP in atherosclerosis is unknown. Methods and Results— To clarify the role of macrophage PLTP in atherogenesis, PLTP was selectively disrupted in hematopoietic cells, including macrophages, by transplantation of bone marrow from PLTP knockout (PLTP−/−) mice into irradiated low-density lipoprotein receptor knockout mice. Selective deficiency of macrophage PLTP (PLTP−M/−M) resulted in a 29% ( P