Effect of macrophage-derived apolipoprotein E on hyperlipidemia and atherosclerosis of LDLR-deficient mice

Shi, Weibin; Wang, Xuping; Wong, Jeffrey A.; Hedrick, Catherine C.; Wong, Howard; Castellani, Lawrence W.; Lusis, Aldons J.

doi:10.1016/j.bbrc.2004.03.037

Cited by 18 publications

(15 citation statements)

References 33 publications

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“…Although the functions of macrophage ABCA1 and apoE in the development of atherosclerosis have been studied extensively [3], [4], [5], [12], [13], [14], [15], their potential combined role in atherosclerotic lesion development is still unexplored. In the present study, we show that macrophage ABCA1 and apoE independently protect against atherosclerotic lesion formation, when normalized for serum cholesterol exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Secreted apoE by macrophages facilitates cellular cholesterol efflux [10] both in the presence and absence of extracellular cholesterol acceptors [11]. Although both pro- and anti-atherogenic functions for macrophage apoE have been described [12], [13], [14], [15], we recently showed that macrophage apoE protects against atherosclerotic lesion development, independent of ABCG1 [5] in LDL receptor knockout (LDLr KO) mice. Moreover, very recently, Zanotti et al showed that expression of apoE only in macrophages is sufficient to promote RCT, emphasizing the pivotal anti-atherogenic role for macrophage apoE [16].…”

Section: Introductionmentioning

confidence: 99%

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Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE

et al. 2011

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AimABCA1 protects against atherosclerosis by facilitating cholesterol efflux from macrophage foam cells in the arterial wall to extracellular apolipoprotein (apo) A-I. In contrast to apoA-I, apoE is secreted by macrophages and can, like apoA-I, induce ABCA1-mediated cholesterol efflux. Yet, the combined effect of macrophage ABCA1 and apoE on lesion development is unexplored.Methods and ResultsLDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/apoE double KO (dKO) mice, their respective single KO's, and wild-type (WT) controls and were challenged with a high-fat/high-cholesterol diet for 9 weeks. In vitro cholesterol efflux experiments showed no differences between ABCA1 KO and dKO macrophages. The serum non-HDL/HDL ratio in dKO transplanted mice was 1.7-fold and 2.4-fold (p<0.01) increased compared to WT and ABCA1 KO transplanted mice, respectively. The atherosclerotic lesion area in dKO transplanted animals (650±94×103 µm2), however, was 1.9-fold (p<0.01) and 1.6-fold (p<0.01) increased compared to single knockouts (ABCA1 KO: 341±20×103 µm2; apoE KO: 402±78×103 µm2, respectively) and 3.1-fold increased (p<0.001) compared to WT (211±20×103 µm2). When normalized for serum cholesterol exposure, macrophage ABCA1 and apoE independently protected against atherosclerotic lesion development (p<0.001). Moreover, hepatic expression levels of TNFα and IL-6 were highly induced in dKO transplanted animals (3.0-fold; p<0.05, and 4.3-fold; p<0.001, respectively). In agreement, serum IL-6 levels were also enhanced in ABCA1 KO transplanted mice (p<0.05) and even further enhanced in dKO transplanted animals (3.1-fold as compared to ABCA1 KO transplanted animals; p<0.05).ConclusionsCombined deletion of macrophage ABCA1 and apoE results in a defect in cholesterol efflux and, compared to ABCA1 KO transplanted mice, elevated serum total cholesterol levels. Importantly, these mice also suffer from enhanced systemic and hepatic inflammation, together resulting in the observed augmented atherosclerotic lesion development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE

et al. 2011

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“…The descending aorta of each mouse was prepared separately, as our laboratory previously described (15,16). Briefly, the vessel was flushed thoroughly with phosphate-buffered saline (PBS), containing 5 U/ml of heparin, through the left ventricle of the heart, cleaned of periadventitial fat and connective tissues, and snap-frozen in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility

Yuan¹,

Miyoshi²,

Bao³

et al. 2009

American Journal of Physiology-Heart and Circulatory Physiology

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W. Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility. Am J Physiol Heart Circ Physiol 296: H1336 -H1343, 2009. First published March 20, 2009 doi:10.1152/ajpheart.01095.2008.-Inbred mouse strains C57BL/6J (B6) and C3H/HeJ (C3H) exhibit a marked difference in atherosclerotic lesion formation when deficient in apolipoprotein E (apoE Ϫ/Ϫ ), and the arterial wall has been identified as a source of the difference in atherosclerosis susceptibility. In the present study, differences in gene expression in aortic walls of the two strains were analyzed by microarrays. Total RNA was extracted from the aorta of 6-wk-old female B6 and C3H apoE Ϫ/Ϫ mice fed a chow or Western diet. There were 1,514 genes in chow fed mice and 590 genes in Western fed mice that were found to be differentially expressed between the two strains. Pathway analysis of differentially expressed genes suggested a role for the calcium signaling pathway in regulating atherosclerosis susceptibility. Oxidized LDL (oxLDL) induced a dose-dependent rise in cytosolic calcium levels in B6 endothelial cells. oxLDL-induced monocyte chemoattractant protein-1 production was inhibited by pretreatment with calcium chelator EGTA or intracellular calcium trapping compound BAPTA, indicating that calcium ions mediate the effect of oxLDL on monocyte chemoattractant protein-1 induction. The present findings demonstrate involvement of the calcium signaling pathway in the inflammatory process of atherogenesis. gene profiling; genetic susceptibility; monocyte chemoattractant protein-1 ATHEROSCLEROSIS IS A CHRONIC inflammatory disease of the large-and medium-sized arteries involving numerous genes, as well as their interactions with the environment. The mouse has been a powerful force in elucidating the genetic basis of atherogenesis. More than 80 genes have been confirmed to play a role in atherosclerosis by using gene-targeted or transgenic mice (21). Inbred mouse strains that display quantitative differences in susceptibility to atherosclerosis or associated traits have also been used to search for genes and pathways that give rise to the traits. C57BL/6 (B6) and C3H/HeJ (C3H) mice are two inbred strains that exhibit marked differences in atherosclerosis susceptibility when fed an atherogenic diet or when deficient in apolipoprotein E (apoE Ϫ/Ϫ ) (8,14). Strain B6 readily develops atherosclerosis, while strain C3H is highly resistant to it. We have observed various differences between the two strains in atherogenic processes involving the arterial wall, including differences in the retention of apoB-containing lipoproteins in the arterial wall (2), in the capacity to oxidize low-density lipoprotein (LDL) (2), and in the expression of proinflammatory genes upon stimulation with oxidized LDL (13). Through aorta transplantation, whereby aortic segments from B6.apoE Ϫ/Ϫ and C3H.apoE Ϫ/Ϫ mice were transplanted into the infrarenal aorta of their F 1 strains, we have demonstrated that th...

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“…Aorta protein was prepared as previously described [10]. Briefly, the aorta was washed thoroughly with phosphate-buffered saline containing 5 U/ml heparin and 1 m M EDTA through the heart, cleaned of periadventitial fat and connective tissues, and snap-frozen in liquid nitrogen.…”

Section: Methodsmentioning

confidence: 99%

Effect of Aging on Fatty Streak Formation in a Diet-Induced Mouse Model of Atherosclerosis

Li¹,

Gilbert²,

Matsumoto³

et al. 2007

J Vasc Res

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Age is considered to be a major risk factor for atherosclerosis, but it is unclear whether age has a direct effect on susceptibility to atherosclerosis. Wild-type mice develop fatty streak lesions in the aortic root only when fed a cholate-containing high fat/cholesterol diet. To investigate the influence of age on fatty streak formation, young (10 weeks) and old (53 weeks) female C57BL/6 mice were fed an atherogenic diet containing 15% fat, 1.25% cholesterol and 0.5% sodium cholate for 12 weeks. Atherosclerotic lesions at the aortic root were measured after cryosections were stained with oil red O. Results showed that old mice developed a comparable size of aortic lesions with young counterparts (5,600 ± 2,480 vs. 6,457 ± 1,537 µm²/section; p = 0.77), although old mice had significantly higher plasma cholesterol levels than young mice on the atherogenic diet (p < 0.05). Plasma levels of soluble vascular cell adhesion molecule 1 were significantly higher in old mice than in young mice on both chow and Western diets (p < 0.005). These data indicate that age has no direct effect on atherosclerosis susceptibility although it is accompanied by elevations in plasma cholesterol and vascular cell adhesion molecule 1 levels in C57BL/6 mice. Thus, increased cardiovascular events with age are probably related to a progressive increase in plaque size rather than to an increase in atherosclerosis susceptibility.

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Effect of macrophage-derived apolipoprotein E on hyperlipidemia and atherosclerosis of LDLR-deficient mice

Cited by 18 publications

References 33 publications

Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE

Augmented Atherogenesis in LDL Receptor Deficient Mice Lacking Both Macrophage ABCA1 and ApoE

Microarray analysis of gene expression in mouse aorta reveals role of the calcium signaling pathway in control of atherosclerosis susceptibility

Effect of Aging on Fatty Streak Formation in a Diet-Induced Mouse Model of Atherosclerosis

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