and references therein). Each of the three major compo-La Jolla, California 92037 nents of the arterial wall, endothelial cells, smooth mus- ‡ Department of Pathology cle cells, and macrophages, are capable of oxidatively University of California modifying LDL to a form that can be recognized by San Diego, California 92093 macrophage scavenger receptors (Steinberg, 1997). A number of mechanisms have been postulated to contribute to cell-mediated oxidation of LDL, including the action of lipoxygenases and the generation of superoxide Summary anion (Steinbrecher et al., 1984; Kuhn et al., 1994; Folcik et al., 1995). The demonstration that anti-oxLDL autoan-Macrophage uptake of oxidized low-density lipoprotein tibodies can be detected in human serum, the presence (oxLDL) is thought to play a central role in foam cell of oxidized fatty acids and cholesterol metabolites in formation and the pathogenesis of atherosclerosis.
atherosclerotic lesions, and the observation that antioxi-We demonstrate here that oxLDL activates PPAR␥dant drugs can slow the progression of atherosclerosis dependent transcription through a novel signaling in experimental animal models all support a central role pathway involving scavenger receptor-mediated partifor oxLDL in the pathogenesis of atherosclerosis. cle uptake. Moreover, we identify two of the major
The LDL particle acquires a number of important biooxidized lipid components of oxLDL, 9-HODE and 13logical activities as a result of oxidative modification in HODE, as endogenous activators and ligands of PPAR␥.
addition to the ability to bind scavenger receptors.
Our data suggest that the biologic effects of oxLDL
OxLDL is both a potent chemoattractant for circulating are coordinated by two sets of receptors, one on the monocytes and a potent inhibitor of resident macrocell surface, which binds and internalizes the particle, phage motility (Quinn et al., 1987). These properties may and one in the nucleus, which is transcriptionally actihelp to explain how monocytes are recruited to and vated by its component lipids. These results suggest trapped within the early atherosclerotic lesion. OxLDL that PPAR␥ may be a key regulator of foam cell gene has also been shown to be a powerful regulator of macexpression.
rophage gene expression. A number of genes involved in the inflammatory response, including those encoding TNF␣, IL-1␣, IL-1, IL-6, and PDGF, are known to be