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

Proceedings of the National Academy of Sciences of the United States of America - Tập 103 Số 10 - Trang 3781-3786 - 2006
Eugene Trogan1,2, Jonathan E. Feig3, Snjezana Doğan3, George H. Rothblat4, Véronique Angeli5, Frank Tacke5, Gwendalyn J. Randolph5, Edward A. Fisher3
1*Marc and Ruti Bell Vascular Biology Program, Leon H. Charney Division of Cardiology/Department of Medicine, New York University School of Medicine, New York, NY 10016;; Graduate School of Biological Sciences and
2Graduate School of Biological Sciences and
3*Marc and Ruti Bell Vascular Biology Program, Leon H. Charney Division of Cardiology/Department of Medicine, New York University School of Medicine, New York, NY 10016;
4Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
5Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029; and

Tóm tắt

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 α 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 abrogatedin vivoby 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 resultsin vivopoint to complex relationships among the immune system, nuclear hormone receptors, and inflammation during regression.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 103 Số 10

3781-3786

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