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

Eugene Trogan, Jonathan E. Feig, Snjezana Dogan, George H. Rothblat, Véronique Angeli, Frank Tacke, Gwendalyn J. Randolph, Edward A. Fisher

Research output: Contribution to journalArticlepeer-review

295 Scopus citations

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 ≈40%, and foam cell content by ≈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 α 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 γ. 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.

Original languageEnglish
Pages (from-to)3781-3786
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number10
DOIs
StatePublished - Mar 7 2006

Keywords

  • Cholesterol efflux
  • Dendritic cell
  • Macrophage
  • Monocyte
  • Nuclear hormone receptor

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