Transcriptional Repression of Atherogenic Inflammation: Modulation by PPARδ

Abstract

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) γ promotes lipid uptake and efflux in these atherogenic cells. In contrast, we found that the closely related receptor PPARδ controls the inflammatory status of the macrophage. Deletion of PPARδ 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 PPARδ controls an inflammatory switch through its association and disassociation with transcriptional repressors. PPARδ and its ligands may thus serve as therapeutic targets to attenuate inflammation and slow the progression of atherosclerosis.