Transcriptional repression of atherogenic inflammation: modulation by PPARdelta.
The formation of an atherosclerotic lesion is mediated by lipid-laden macrophages (foam cells), which also establish chronic inflammation associated with lesion progression. The peroxisome proliferator-activated receptor (PPAR) gamma promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARdelta controls the inflammatory status of the macrophage. Deletion of PPARdelta from foam cells increased the availability of inflammatory suppressors, which in turn reduced atherosclerotic lesion area by more than 50%. We propose an unconventional ligand-dependent transcriptional pathway in which PPARdelta controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARdelta and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.
Lee
Chih-Hao
CH
Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Chawla
Ajay
A
Urbiztondo
Ned
N
Liao
Debbie
D
Boisvert
William A
WA
Evans
Ronald M
RM
Curtiss
Linda K
LK
D000818:Animals; D001161:Arteriosclerosis / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D018450:Disease Progression; D005487:Foam Cells / Q000502:physiology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000209:etiology*; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; D007375:Interleukin-1; D008024:Ligands; D008055:Lipids; D011518:Proto-Oncogene Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors; D002784:Cholesterol; D020780:Matrix Metalloproteinase 9