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. 2006 Mar 7;103(10):3781-6.
doi: 10.1073/pnas.0511043103. Epub 2006 Mar 1.

VSports注册入口 - Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Eugene Trogan  1 , Jonathan E Feig, Snjezana Dogan, George H Rothblat, Véronique Angeli, Frank Tacke, Gwendalyn J Randolph, Edward A Fisher
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Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice

Eugene Trogan et al. Proc Natl Acad Sci U S A. .

Abstract

Atherosclerosis regression is an important clinical goal. In previous studies of regression in mice, the rapid loss of plaque foam cells was explained by emigration to lymph nodes, a process reminiscent of dendritic cells. In the present study, plaque-containing arterial segments from apoE-/- mice were transplanted into WT recipient normolipidemic mice or apoE-/- mice VSports手机版. Three days after transplant, in the WT regression environment, plaque size decreased by approximately 40%, and foam cell content by approximately 75%. In contrast, both parameters increased in apoE-/- recipients. Foam cells were isolated by laser capture microdissection. In WT recipients, there were 3- to 6-fold increases in foam cells of mRNA for liver X receptor alpha and cholesterol efflux factors ABCA1 and SR-BI. Although liver X receptor alpha was induced, there was no detectable expression of its putative activator, peroxisome proliferator-activated receptor gamma. Expression levels of VCAM or MCP-1 were reduced to 25% of levels in pretransplant or apoE-/- recipient samples, but there was induction at the mRNA and protein levels of chemokine receptor CCR7, an essential factor for dendritic cell migration. Remarkably, when CCR7 function was abrogated in vivo by treatment of WT recipients with antibodies to CCR7 ligands CCL19 and CCL21, lesion size and foam cell content were substantially preserved. In summary, in foam cells during atherosclerosis regression, there is induction of CCR7 and a requirement for its function. Taken with the other gene expression data, these results in vivo point to complex relationships among the immune system, nuclear hormone receptors, and inflammation during regression. .

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Conflict of interest statement

Conflict of interest statement: No conflicts declared.

Figures

Fig. 1.
Fig. 1.
Reversal of dyslipidemia decreases plaque size and foam cell content. (A) Representative sections of aortic transplant segments from baseline (apoE−/−), and WT and apoE−/− recipients at 3 and 7 days after transplantation. Sections were immunostained with anti-CD68 antibody (red). (B) Quantification of intimal (outset bars) and foam cell areas (inset bars). N represents the number of animals in each group.
Fig. 2.
Fig. 2.
Up-regulation of the chemokine receptor CCR7 in foam cells in the regression environment. Sections were prepared from the aortic arches of baseline apoE−/− mice or from the grafts 3 days after transplantation into WT or apoE−/− recipients. (Upper) Staining results using the CCL19-Fc chimeric protein are shown. “L” and “M” indicate lumen and media. In an adjacent section, the CCR7+ area corresponded to staining for CD68 (data not shown). Results from baseline plaques were similar to those in the apoE−/− recipient (data not shown). (Lower) CCR7 and cyclophilin A mRNA levels were measured by QRT-PCR in laser captured CD68+ cells. The levels were then converted to final values based on standard curves for these RNAs in total RNA isolated from spleen. Shown are the mean ± SEM of the CCR7/cyclophilin A ratios from two pools of RNA, each pool consisting of three independent mice.
Fig. 3.
Fig. 3.
Functional role of CCR7 in atherosclerosis regression. Donor apoE−/− mice were placed on the WD and, at 20 weeks of age, the aortic arches were taken either for baseline data (labeled as “Pretransplant”; n = 5 mice) or transplantation into WT recipients. Half of the recipient mice were injected ≈2 h before surgery and shortly after with goat anti-CCL-19 and anti-CCL-21 (labeled as “CCL19/21 antibodies” in Upper and “anti-19/21” in the graphs, n = 11), the other half with preimmune (“Control serum,” n = 7) goat IgG. At 3 days after transplant, grafts were harvested and sectioned for morphometric and immunostaining analyses. (Upper) Representative CD68-immunostained sections from each group. (Lower) Graphical summaries for the groups (means ± SEM). Statistical analysis was by ANOVA and the Bonferroni test of multiple comparisons. ∗, P < 0.001 vs. pretransplant; ∗∗, P < 0.001 vs. anti-19/21.
Fig. 4.
Fig. 4.
Regulation of the expression of genes associated with cholesterol efflux and inflammation in foam cells after the reversal of dyslipidemia. Foam cells were laser captured from sections of aortic arches of baseline apoE−/− mice or of grafts 3 days after transplantation into WT or apoE−/− recipients. Total RNA was isolated, and the indicated mRNA levels were measured by QRT-PCR as described in Fig. 2, except that the final ratios for the baseline samples were set to 100%. Shown are the results for genes associated with cholesterol efflux (A) and inflammation (B). Data are based on two pools of RNA, each pool consisting of three independent mice, and are expressed as fold change over baseline (mean ± SEM).
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