Abstract 827: Total Body ABCG1-Deficiency Increases Atherosclerotic Lesion Development In LDL-Receptor Knockout Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Illiana Meurs ◽  
Ruud Out ◽  
Menno Hoekstra ◽  
Reeni B Hildebrand ◽  
Theo J Van Berkel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Lipid Accumulation ◽  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Chow Diet ◽  
Lesion Development ◽  
Total Body ◽  
Atherosclerotic Lesion Development

ATP-binding cassette transporter G1 (ABCG1) facilitates the efflux of cholesterol from macrophages to HDL. As ABCG1 plays a role in preventing cellular lipid accumulation, macrophage ABCG1 expression has been suggested to protect against atherosclerosis. In bone marrow transplantation studies, however, we and others obtained different effects of specific macrophage ABCG1-deficiency on atherosclerotic lesion development under different experimental settings. The objective of this study was to further define the effect of ABCG1-deficiency on lipid metabolism and atherosclerotic lesion development. ABCG1 knockout (KO) mice upon atherogenic diet feeding develop only modest atherosclerotic lesions, therefore, we recently cross-bred ABCG1 KO mice with LDL-receptor KO (LDLr KO) mice. LDLr KO and LDLr/ABCG1 double KO (dKO) littermates were fed a high-fat, high-cholesterol Western-type diet (WTD) containing 0.25% cholesterol and 15% fat for 10 weeks to induce atherosclerotic lesion formation. Both on chow diet and on WTD, serum lipid levels and lipoprotein profiles showed no significant differences between the LDLr KO and LDLr/ABCG1 dKO mice. However, after 10 weeks of diet feeding, a significant 1.5-fold increase in atherosclerotic lesion size was observed in the aortic root of LDLr/ABCG1 dKO mice (130 ± 12x10 3 μm 2 [n = 8] compared to 88 ± 11x10 3 μm 2 [n=7] for LDLr KO mice; p =0.026). In addition, macrophage-rich areas of the lungs and spleens of LDLr/ABCG1 dKO mice exhibited excessive lipid accumulation compared with LDLr KO mice. Furthermore, in vitro studies using bone marrow derived macrophages of LDLr KO and LDLr/ABCG1 dKO mice showed that disruption of ABCG1 results in a 15% decrease in cholesterol efflux to HDL ( p< 0.001), whereas the cholesterol efflux to ApoAI was unaffected. These studies reveal that total-body ABCG1 deficiency leads to increased atherosclerotic lesion development and massive lipid accumulation in macrophages of the lung and spleen, possibly due to impaired efflux of cholesterol from macrophages deficient in ABCG1. In conclusion, the expression of ABCG1 protects against atherosclerotic lesion development.

Abstract 1721: Deletion of Both Macrophage ABCG1 and ApoE Independently Promotes Atherosclerotic Lesion Development in LDL Receptor Knockout Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ruud Out ◽  
Bart Lammers ◽  
Reeni B. Hildebrand ◽  
Carmel M. Quinn ◽  
David Williamson ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Independent Effect ◽  
High Cholesterol Diet ◽  
Moderate Increase ◽  
Lesion Development ◽  
Macrophage Cholesterol Efflux ◽  
Atherosclerotic Lesion Development

Objective ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein E (apoE) play a role in macrophage cholesterol efflux and consequently the development of atherosclerosis. Although a possible interaction between ABCG1 and apoE in cholesterol efflux was postulated, the combined action of these proteins in atherosclerosis is still unclear. Methods and Results 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. After feeding a high-fat/high-cholesterol diet for 6 weeks, no differences were found in serum lipid levels. However, the mean atherosclerotic lesion area in dKO transplanted animals (187 ± 18 × 10 3 μ m 2 ) was 1.4-fold (p < 0.01) increased compared to single knockouts (ABCG1 KO: 138 ± 5 × 10 3 μm 2 ; apoE KO: 131 ± 7 × 10 3 μm 2 ) and 1.9-fold (p< 0.001) as compared to WT controls (97 ± 15 × 10 3 μm 2 ). In vitro cholesterol efflux experiments confirmed that combined deletion of ABCG1 and apoE resulted in a larger attenuation of macrophage cholesterol efflux to HDL as compared to single knockouts. Conclusions Deletion of macrophage ABCG1 or apoE does lead to a moderate increase in atherosclerotic lesion development while combined deletion of ABCG1 and apoE induces a more dramatic increase in atherosclerosis. These results indicate an added, independent effect for both macrophage ABCG1 and apoE in atherosclerosis.

scholarly journals Hematopoietic upstream stimulating factor 1 deficiency is associated with increased atherosclerosis susceptibility in LDL receptor knockout mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Menno Hoekstra ◽  
Baoyan Ren ◽  
Pirkka-Pekka Laurila ◽  
Reeni B. Hildebrand ◽  
Jarkko Soronen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Knockout Mice ◽  
Ldl Receptor ◽  
Atherosclerotic Lesion ◽  
Functional Expression ◽  
Upstream Stimulatory Factor ◽  
Wild Type Littermate ◽  
Brown Adipose ◽  
Total Body ◽  
Ldl Receptor Knockout Mice

AbstractTotal body upstream stimulatory factor 1 (USF1) deficiency in mice is associated with brown adipose tissue activation and a marked protection against the development of obesity and atherosclerotic lesions. Functional expression of USF1 has also been detected in monocytes and monocyte-derived macrophages. In the current study we therefore tested whether selective hematopoietic USF1 deficiency can also beneficially impact the development of atherosclerosis. For this purpose, LDL receptor knockout mice were transplanted with bone marrow from USF1 knockout mice or their wild-type littermate controls and subsequently fed a Western-type diet for 20 weeks to stimulate atherosclerotic lesion development. Strikingly, absence of USF1 function in bone marrow-derived cells was associated with exacerbated blood leukocyte (+ 100%; P < 0.01) and peritoneal leukocyte (+ 50%; P < 0.05) lipid loading and an increased atherosclerosis susceptibility (+ 31%; P < 0.05). These effects could be attributed to aggravated hyperlipidemia, i.e. higher plasma free cholesterol (+ 33%; P < 0.001) and cholesteryl esters (+ 39%; P < 0.001), and the development of hepatosteatosis. In conclusion, we have shown that hematopoietic USF1 deficiency is associated with an increased atherosclerosis susceptibility in LDL receptor knockout mice. These findings argue against a contribution of macrophage-specific USF1 deficiency to the previously described beneficial effect of total body USF1 deficiency on atherosclerosis susceptibility in mice.

Abstract 3693: Early Growth Response Gene-1 Deficiency In Bone-marrow-derived Cells Reduces Macrophage Accumulation And Atherosclerotic Lesion Formation In A Hyperlipidemic Mouse Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Michael R Preusch ◽  
Claudia Albrecht ◽  
Gotz Hofmann ◽  
Erwin Blessing ◽  
Hugo A Katus ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Atherosclerotic Lesion ◽  
Lesion Development ◽  
Early Growth Response ◽  
Atherosclerotic Lesions ◽  
Early Growth Response Gene ◽  
Bone Marrow Derived Cells ◽  
Deficient Mice ◽  
Atherosclerotic Lesion Development ◽  
Macrophage Accumulation

Early growth response gene-1 (Egr-1), a prototype of a family of zinc-finger transcription factors, is a master regulator of many genes which play important roles in cardiovascular diseases. Within atherosclerotic lesions Egr-1 is expressed in several cell types, such as smooth muscle cells, endothelial cells and monocytes/macrophages. Since macrophages play a pivotal role in atherosclerotic lesion development, this study investigated the effects of Egr-1-deficiency within bone-marrow derived cells on the development of atherosclerosis in a hyperlipidemic mouse model. Therefore we transplanted bone-marrow from Egr-1 deficient mice and wild type controls into lethally irradiated low-density lipoprotein receptor deficient mice. After 20 weeks on a western diet atherosclerotic lesions within the aortic sinus and gene expression of inflammatory genes in the aortas of the recipients were evaluated. Mice receiving Egr-1 deficient bone-marrow had less atherosclerotic lesion development compared with mice receiving wild type bone-marrow (318 736 ± 98 910μm 2 vs. 404 539 ± 92 408μm 2 , p<0.05). The size of the necrotic core within the lesions was also reduced. Immunohistochemistry revealed that mice receiving Egr-1 deficient bone-marrow had less macrophages in comparison to controls. Gene expression analysis in the aortas of the mice demonstrated reduced expression of Vascular Cell Adhesion Molecule (VCAM-1), an important adhesion molecule during the development of atherosclerosis. These results were validated with in vitro studies where Egr-1-deficient peritoneal macrophages revealed less VCAM-1 mRNA expression after stimulation with lipopolysaccharide in comparison to wildtype macrophages. This study demonstrates that bone-marrow derived Egr-1 promotes macrophage accumulation and atherosclerotic lesion development possible over an increased expression of VCAM-1.

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