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

被引:289
作者
Trogan, E
Feig, JE
Dogan, S
Rothblat, GH
Angeli, V
Tacke, F
Randolph, GJ
Fisher, EA
机构
[1] NYU, Sch Med, Leon H Charney Div Cardiol, Marc & Ruti Bell Vasc Biol Program,Dept Med, New York, NY 10016 USA
[2] CUNY Mt Sinai Sch Med, Grad Sch Biol Sci, New York, NY 10029 USA
[3] CUNY Mt Sinai Sch Med, Dept Gene & Cell Med, New York, NY 10029 USA
[4] Univ Penn, Sch Med, Dept Pediat, Philadelphia, PA 19104 USA
关键词
cholesterol efflux; dendritic cell; macrophage; monocyte; nuclear hormone receptor;
D O I
10.1073/pnas.0511043103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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. Three days after transplant, in the WT regression environment, plaque size decreased by approximate to 40%, and foam cell content by approximate to 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 a and cholesterol efflux factors, ABCA1 and SR-BI. Although liver X receptor a 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.
引用
收藏
页码:3781 / 3786
页数:6
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