title: Macrophage expression of peroxisome proliferator-activated receptor-alpha reduces atherosclerosis in low-density lipoprotein receptor-deficient mice.
abstract: BACKGROUND
  The peroxisome proliferator-activated receptor-alpha (PPARalpha) plays important roles in lipid metabolism, inflammation, and atherosclerosis. PPARalpha ligands have been shown to reduce cardiovascular events in high-risk subjects. PPARalpha expression by arterial cells, including macrophages, may exert local antiatherogenic effects independent of plasma lipid changes.
  
  
  RESULTS
  To examine the contribution of PPARalpha expression by bone marrow-derived cells in atherosclerosis, male and female low-density lipoprotein receptor-deficient (LDLR(-/-)) mice were reconstituted with bone marrow from PPARalpha(-/-) or PPARalpha(+/+) 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 PPARalpha(-/-) --> LDLR(-/-) mice was significantly increased (44% and 46%, respectively) compared with controls. Male PPARalpha(-/-) --> LDLR(-/-) mice also had larger (44%) atherosclerotic lesions in the proximal aorta than male PPARalpha(+/+) --> LDLR(-/-) mice. Peritoneal macrophages from PPARalpha(-/-) mice had increased uptake of oxidized LDL and decreased cholesterol efflux. PPARalpha(-/-) macrophages had lower levels of scavenger receptor B type I and ABCA1 protein expression and an accelerated response of nuclear factor-kappaB-regulated inflammatory genes. A laser capture microdissection analysis verified suppressed scavenger receptor B type I and increased nuclear factor-kappaB gene expression levels in vivo in atherosclerotic lesions of PPARalpha(-/-) --> LDLR(-/-) mice compared with the lesions of control PPARalpha(+/+) --> LDLR(-/-) mice.
  
  
  CONCLUSIONS
  These data demonstrate that PPARalpha expression by macrophages has antiatherogenic effects via modulation of cell cholesterol trafficking and inflammatory activity.
authors.affiliation: Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn, USA. vladimir.babaev@vanderbilt.edu
authors.forename: Vladimir R
authors.initials: VR
authors.lastname: Babaev
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ishiguro
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.forename: Patricia G
authors.initials: PG
authors.lastname: Yancey
authors.forename: Dwayne E
authors.initials: DE
authors.lastname: Dove
authors.forename: William J
authors.initials: WJ
authors.lastname: Kovacs
authors.forename: Clay F
authors.initials: CF
authors.lastname: Semenkovich
authors.forename: Sergio
authors.initials: S
authors.lastname: Fazio
authors.forename: MacRae F
authors.initials: MF
authors.lastname: Linton
mesh_terms: D000818:Animals; D001018:Aortic Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D016026:Bone Marrow Transplantation; D002087:Butyrates / Q000494:pharmacology; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007249:Inflammation / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047493:PPAR alpha / Q000819:agonists / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011828:Radiation Chimera; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics
chemical_list: D002087:Butyrates; C453899:GW 7647; D008077:Lipoproteins, LDL; D047493:PPAR alpha; D010671:Phenylurea Compounds; D011743:Pyrimidines; D011973:Receptors, LDL; C006253:pirinixic acid