Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Shimano, Hitoshi; Ohsuga, Jun-ichi; Shimada, Masako; Namba, Yoshio; Gotoda, Takanari; Harada, Kenji; Katsuki, Motoya; Yazaki, Yoshio; Yamada, Nobuhiro

doi:10.1172/jci117687

Cited by 125 publications

(95 citation statements)

References 39 publications

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“…The involvement of apoE in mediating cholesterol efflux from macrophages was first identified by Basu et al (1982) and is now supported by several lines of evidence (Shimano et al 1995). ApoE seems to promote cholesterol efflux when endogenously expressed and to a lesser extent when exogenously added (Lin et al 1999), and it has been hypothesised that the macrophage and non-macrophage apoE act via divergent mechanisms (Lin et al 1999) that work in parallel (Dove et al 2005).…”

Section: Apoe and Cellular Cholesterol Efflux And Reverse Cholesterolmentioning

confidence: 94%

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

et al. 2007

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Cardiovascular risk is determined by the complex interactions between genetic and environmental factors. The apoE genotype represents the most-widely-studied single nucleotide polymorphism in relation to CVD risk, with > 3600 publications cited in PubMed. Although originally described as a mediator of lipoprotein metabolism, the lipoprotein-independent functions of apoE are being increasingly recognised, with limited data available on the potential impact of genotype on these metabolic processes. Furthermore, although meta-analyses suggest that apoE4 carriers may have a 40-50% increased CVD risk, the associations reported in individual studies are highly heterogeneous and it is recognised that environmental factors such as smoking status and dietary fat composition influence genotype-phenotype associations. However, information is often derived from observational studies or small intervention trials in which retrospective genotyping of the cohort results in small group sizes in the rarer E2 and E4 subgroups. Either larger well-standardised intervention trials or smaller trials with prospective recruitment according to apoE genotype are needed to fully establish the impact of diet on genotype-CVD associations and to establish the potential of dietary strategies such as reduced total fat, saturated fat, or increased antioxidant intakes to counteract the increased CVD burden in apoE4 carriers. ApoE genotype: CVD: Dietary fat: Oxidative status: InflammationThe impact of single nucleotide polymorphisms on risk of chronic diseases such as CVD, and the ability of dietary factors to manipulate genotype-phenotype associations, is being increasingly recognised. Undoubtedly, the mostwidely-studied gene variant in relation to CVD is the apoE e (e2, e3, e4) genotype. Since its discovery in 1973 the central role of the apoE protein in lipoprotein metabolism has been comprehensively investigated and reported. The 40-50 % higher risk of CVD in apoE4 carriers (Song et al. 2004) has been traditionally attributed to moderately higher circulating cholesterol and TAG levels. However, it is becoming increasingly recognised that an effect on lipoprotein metabolism alone cannot explain the disease differential and that the impact of an apoE4 genotype is largely lipoprotein independent. Roles of macrophagederived apoE protein on vascular health and atherogenesis are being identified, with apoE thought to impact on oxidative status and in an autocrine and paracrine manner affect macrophage, vascular smooth muscle cell, endothelial cell and platelet function. An impact of genotype on these localised functions of apoE could in part explain the impact of genotype on CVD pathology, as will be discussed.Additionally, apoE genotype has been shown to affect the responsiveness to the total fat content and fatty acid composition of the diet. Manipulation of dietary fat content may serve as a means of reducing the increased CVD burden associated with an apoE4 genotype.

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Section: Apoe and Cellular Cholesterol Efflux And Reverse Cholesterolmentioning

confidence: 94%

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

et al. 2007

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“…[34][35][36][38][39][40] Although adenovirus-based gene transfer strategies are powerful, they raise major safety concerns when envisioned for treating long-term human diseases such as atherosclerosis. 37 Also, gene expression from these vectors is only transient and strong immunological responses increase the risk of further injections.…”

Section: Figure 3 Cardiac Sections From Control and Experimental Apoementioning

confidence: 99%

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E

Cioffi¹,

Sturtz²,

Wittmer³

et al. 1999

Gene Ther

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A major focus in gene therapy has been the use of recomand lesions at a young age. After transplantation of the binant viruses to deliver genes in vivo. Although this apoE secreting Pro 175 endothelial cells into apoEapproach shows much promise, there are many safety deficient mice, serum cholesterol levels were measured at concerns associated with the use of viral materials in the 2 week intervals. During the 3 months after the initiation of treatment of human diseases. Our alternative cell-based these experiments, levels of cholesterol in the animals havgene therapy approach utilizes endothelial cells (Pro 175) ing received the apoE secreting endothelial cells were statisolated from the murine embryonic yolk sac. These endoistically lower compared with the levels of age-matched thelial cells were evaluated for their potential use in gene controls having received non-secreting endothelial cells. therapy as a gene delivery platform. As a test model, we Concomitant with cholesterol reduction, atherosclerotic used these cells to deliver apolipoprotein E (apoE) in the aortic plaques were noticeably reduced in the experimental murine apoE knockout atherosclerosis model. The lack of apoE+ animals. These results highlight the potential of apoE protein in these animals results in high levels of these unique endothelial cells as an efficient delivery serum cholesterol and formation of severe aortic plaques platform for somatic gene therapy.

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“…Transgenic mice overexpressing rat apoE displayed marked resistance to diet-induced hypercholesterolemia and did not develop atherosclerosis (1,2). In contrast, mice with targeted disruption of the apoE gene developed spontaneous atherosclerosis even under basal low fat/low cholesterol dietary conditions (3,4).…”

mentioning

confidence: 99%

Apolipoprotein E Binding to Low Density Lipoprotein Receptor-related Protein-1 Inhibits Cell Migration via Activation of cAMP-dependent Protein Kinase A

Zhu

Hui

2003

Journal of Biological Chemistry

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Smooth muscle cell migration and proliferation contribute to neointimal hyperplasia and vascular stenosis after endothelial denudation. Previous studies revealed that apolipoprotein E (apoE) is an effective inhibitor of platelet-derived growth factor-directed smooth muscle cell migration and proliferation and that the anti-migratory function is mediated via apoE binding to low density lipoprotein receptor-related protein-1 (LRP-1). This study was undertaken to identify the intracellular pathway by which apoE binding to LRP-1 results in inhibition of smooth muscle cell migration. The results showed that apoE increased intracellular cAMP levels 3-fold after 5 min, and the increase was sustained for more than 1 h. As a consequence, apoE also increased protein kinase A (PKA) activity in smooth muscle cells. Importantly, suppression of PKA activity with a cellpermeable peptide inhibitor of PKA abolished the inhibitory effect of apoE on smooth muscle cell migration. These results indicated that apoE inhibition of smooth muscle cell migration is mediated via the activation of cAMP-dependent PKA. Additional experiments revealed that apoE also inhibited fibroblasts migration toward platelet-derived growth factor by a similar mechanism of cAMP-dependent PKA activation. It is noteworthy that apoE failed to increase cAMP levels or inhibit migration of LRP-1-negative mouse embryonic fibroblasts and LRP-1-deficient smooth muscle cells. Taken together, these findings established the mechanism by which apoE inhibits cell migration, i.e. via cAMP-dependent protein kinase A activation as a consequence of its binding to LRP-1.The importance of apolipoprotein E (apoE) 1 in protecting against atherosclerosis was convincingly demonstrated by studies with experimental animals. Transgenic mice overexpressing rat apoE displayed marked resistance to diet-induced hypercholesterolemia and did not develop atherosclerosis (1, 2). In contrast, mice with targeted disruption of the apoE gene developed spontaneous atherosclerosis even under basal low fat/low cholesterol dietary conditions (3, 4). Atherosclerosis in apoE-null mice could be prevented by increasing circulating apoE levels through recombinant adenovirus-mediated apoE gene transfer to the liver (5). The decrease in atherosclerosis in this model was accompanied by decreased total cholesterol, very low density lipoprotein, and intermediate density lipoprotein levels (5). Although these results seemed to suggest that apoE prevents atherosclerosis by lowering plasma cholesterol levels, atherosclerosis was found to be more severe in cholesterol-fed apoE ϩ/Ϫ mice than in cholesterol-fed apoE ϩ/ϩ mice despite the relative similar plasma cholesterol level in the two groups (4, 6). Additionally, transgenic expression of apoE in the arterial wall inhibited atheroma formation and severity without affecting plasma cholesterol level in cholesterol-fed C57BL/6 mice (1). Subsequent studies showed that low levels of apoE secreted by the adrenal gland also inhibited atherosclerosis without correcting...

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Inhibition of diet-induced atheroma formation in transgenic mice expressing apolipoprotein E in the arterial wall.

Cited by 125 publications

References 39 publications

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

ApoE genotype, cardiovascular risk and responsiveness to dietary fat manipulation

A novel endothelial cell-based gene therapy platform for the in vivo delivery of apolipoprotein E

Apolipoprotein E Binding to Low Density Lipoprotein Receptor-related Protein-1 Inhibits Cell Migration via Activation of cAMP-dependent Protein Kinase A

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