Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice.
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 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.
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, USA.
Eugene
E
Trogan
Jonathan E
JE
Feig
Snjezana
S
Dogan
George H
GH
Rothblat
Véronique
V
Angeli
Frank
F
Tacke
Gwendalyn J
GJ
Randolph
Edward A
EA
Fisher
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D001693:Biological Transport, Active; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000037:antagonists & inhibitors; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000473:pathology; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; C515460:CCL19 protein, human; C515478:CCL21 protein, human; C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515479:Ccl21c protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054421:Chemokine CCL21; D019742:Chemokines, CC; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D002784:Cholesterol; D000077205:Pioglitazone