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

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. Three days after transplant, in the WT regression environment, plaque size decreased by Ϸ40%, and foam cell content by Ϸ75%. 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 ␣ and cholesterol efflux factors ABCA1 and SR-BI. Although liver X receptor ␣ was induced, there was no detectable expression of its putative activator, peroxisome proliferator-activated receptor ␥. 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.cholesterol efflux ͉ dendritic cell ͉ macrophage ͉ monocyte ͉ nuclear hormone receptor M ouse models of atherosclerosis regression are relatively few.However, similarities between atherosclerosis in humans and in mice deficient in apolipoprotein E (apoE Ϫ/Ϫ ) or the LDL receptor (e.g., see ref. 1) suggest that molecular mechanisms underlying regression in mouse models could be relevant to the reduction of the large plaque burden in the middle-aged and older human population.We have previously described a mouse model of regression. First, plaques were allowed to develop in apoE Ϫ/Ϫ mice, then a segment of either thoracic aortic (2) or aortic arch (3, 4) was transplanted into the abdominal aorta of a WT recipient, quickly changing the plasma lipid environment from hyper to normolipidemia. As a control, an aortic segment was transplanted into an apoE Ϫ/Ϫ mouse. By 1 month, in the regression environment (WT recipient), essentially all of the foam cells disappeared from plaques (4), with many no longer visible after 3 days (5). In contrast, in the progression environment (apoE Ϫ/Ϫ recipient), plaque size and foam cell content increased over time.In a recent study, we showed that the rapid depletion of foam cells in the regression environment was correlated with a substantial number of these cells emigrating to lymph nodes (5). Interestingly, the emigrating cells expressed markers of den...

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