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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2003;23:475.)
© 2003 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Activation of Peroxisome Proliferator–Activated Receptor Gamma and Retinoid X Receptor Results in Net Depletion of Cellular Cholesteryl Esters in Macrophages Exposed to Oxidized Lipoproteins

C.A. Argmann; C.G. Sawyez; C.J. McNeil; R.A. Hegele; M.W. Huff

From the Departments of Medicine and Biochemistry and Robarts Research Institute at the University of Western Ontario, London, Ontario, Canada.

Correspondence to M.W. Huff, Robarts Research Institute, Rm 4-16, 100 Perth Dr, London, Ontario, Canada, N6A 5K8. E-mail: mhuff{at}uwo.ca

Objective— Peroxisome proliferator–activated receptor gamma (PPAR), a ligand-activated transcription factor, has pleiotropic effects, including regulation of macrophage differentiation and lipid homeostasis. The PPAR ligands, thiazolidinediones (TZDs), attenuate atherosclerosis in mice by uncertain mechanisms. The objective of this study was to determine whether activation of PPAR or its obligate heterodimer, retinoid X receptor (RXR), modulates macrophage foam cell formation induced by oxidized (ox) lipoproteins.

Methods and Results— Incubation of THP-1 macrophages with oxHTG-VLDL, oxREM, or oxLDL increased cellular cholesteryl ester over 6-fold. Preincubation with the TZD, ciglitazone, the RXR-specific ligand, 9-cis retinoic acid (9cRA) or the combination reduced CE mass accumulation by up to 65%. Ciglitazone and 9cRA increased CD36 mRNA (up to 4-fold); however, uptake of [¹²⁵I]oxLDL was only modestly enhanced (up to 1.8-fold) becaues of a concomitant PPAR:RXR–induced decrease in SRAI/II activity (up to 40%). This suggested that PPAR:RXR activation inhibited cholesteryl ester accumulation by enhancing cholesterol efflux. Ciglitazone and 9cRA were found to increase the expression of ATP-binding cassette proteins A1 and G1, resulting in enhanced cholesterol efflux to lipoprotein-deficient serum, apoAI and HDL₃.

Conclusions— PPAR and/or RXR activation inhibit foam cell formation through enhanced cholesterol efflux despite increased oxLDL uptake. These observations explain the reduced atherosclerosis in TZD-treated mice and may extend the therapeutic implications of these ligands.

Key Words: macrophages • oxidized lipoproteins • PPAR • atherosclerosis

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