PPARdelta regulates multiple proinflammatory pathways to suppress atherosclerosis.
Lipid homeostasis and inflammation are key determinants in atherogenesis, exemplified by the requirement of lipid-laden, foam cell macrophages for atherosclerotic lesion formation. Although the nuclear receptor PPARdelta has been implicated in both systemic lipid metabolism and macrophage inflammation, its role as a therapeutic target in vascular disease is unclear. We show here that orally active PPARdelta agonists significantly reduce atherosclerosis in apoE(-/-) mice. Metabolic and gene expression studies reveal that PPARdelta attenuates lesion progression through its HDL-raising effect and anti-inflammatory activity within the vessel wall, where it suppresses chemoattractant signaling by down-regulation of chemokines. Activation of PPARdelta also induces the expression of regulator of G protein signaling (RGS) genes, which are implicated in blocking the signal transduction of chemokine receptors. Consistent with this, PPARdelta ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPARdelta antagonizes multiple proinflammatory pathways and suggest PPARdelta-selective drugs as candidate therapeutics for atherosclerosis.
Barish
Grant D
GD
Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Atkins
Annette R
AR
Downes
Michael
M
Olson
Peter
P
Chong
Ling-Wa
LW
Nelson
Mike
M
Zou
Yuhua
Y
Hwang
Hoosang
H
Kang
Heonjoong
H
Curtiss
Linda
L
Evans
Ronald M
RM
Lee
Chih-Hao
CH
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D001057:Apolipoproteins E; D018925:Chemokines; D008076:Cholesterol, HDL; D047494:PPAR delta