Macrophage expression of peroxisome proliferator-activated receptor-α reduces atherosclerosis in low-density lipoprotein receptor-deficient mice

Background - The peroxisome proliferator - activated receptor-alpha (PPAR alpha) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPAR alpha ligands have been shown to reduce cardiovascular events in high-risk subjects. PPAR alpha expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes. Methods and Results - To examine the contribution of PPAR alpha expression by bone marrow - derived cells in atherosclerosis, male and female low-density lipoprotein receptor - deficient (LDLR-/-) mice were reconstituted with bone marrow from PPAR alpha(-/-) or PPAR alpha(-/-) mice and challenged with a high-fat diet. Although serum lipids and lipoprotein profiles did not differ between the groups, the size of atherosclerotic lesions in the distal aorta of male and female PPAR alpha(-/-)-> LDLR-/- mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPAR alpha(-/-)-> LDLR-/- mice also had larger ( 44%) atherosclerotic lesions in the proximal aorta than male PPAR alpha(-/-)-> LDLR-/- mice. Peritoneal macrophages from PPAR alpha(-/-) mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPAR alpha(-/-) macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-kappa B-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-kappa B gene expression levels in vivo in atherosclerotic lesions of PPAR alpha(-/-)-> LDLR-/- mice compared with the lesions of control PPAR alpha(-/-)-> LDLR-/- mice. Conclusions - These data demonstrate that PPAR alpha(-/-) expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.