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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
PPAR
regulates multiple proinflammatory pathways to suppress atherosclerosis
*Howard Hughes Medical Institute, Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Francisco, CA 94121; Department of Biology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093; Marine Biotechnology Laboratory, Center for Marine Natural Products and Drug Discovery, School of Earth and Environmental Sciences, Seoul National University NS-80, Seoul 151-747, Korea; ¶Department of Immunology and Vascular Biology, Scripps Research Institute, La Jolla, CA 92037; and **Department of Genetics and Complex Diseases, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115
Contributed by Ronald M. Evans, December 23, 2007 (received for review September 5, 2007)
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 PPAR
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 PPAR agonists significantly reduce atherosclerosis in apoE–/– mice. Metabolic and gene expression studies reveal that PPAR 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 PPAR 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, PPAR ligands repress monocyte transmigration and macrophage inflammatory responses elicited by atherogenic cytokines. These results reveal that PPAR antagonizes multiple proinflammatory pathways and suggest PPAR-selective drugs as candidate therapeutics for atherosclerosis.
inflammation | ligand | mouse | nuclear | receptor
The authors declare no conflict of interest.
||To whom correspondence may be addressed. E-mail: evans{at}salk.edu or clee{at}hsph.harvard.edu
© 2008 by The National Academy of Sciences of the USA
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