title: Reversal of hyperlipidemia with a genetic switch favorably affects the content and inflammatory state of macrophages in atherosclerotic plaques.
abstract: BACKGROUND
  We previously showed that the progression of atherosclerosis in the Reversa mouse (Ldlr(-/-Apob100/100Mttpfl/fl) Mx1Cre(+/+)) was arrested when the hyperlipidemia was normalized by inactivating the gene for microsomal triglyceride transfer protein. Here, we tested whether atherosclerosis would regress if the lipid levels were reduced after advanced plaques formed.
  
  
  RESULTS
  Reversa mice were fed an atherogenic diet for 16 weeks. Plasma lipid levels were then reduced. Within 2 weeks, this reduction led to decreased monocyte-derived (CD68(+)) cells in atherosclerotic plaques and was associated with emigration of these cells out of plaques. In addition, the fall in lipid levels was accompanied by lower plaque lipid content and by reduced expression in plaque CD68(+) cells of inflammatory genes and higher expression of genes for markers of antiinflammatory M2 macrophages. Plaque composition was affected more than plaque size, with the decreased content of lipid and CD68(+) cells balanced by a higher content of collagen. When the reduced lipid level was combined with the administration of pioglitazone to simulate the clinical aggressive lipid management and proliferator-activated receptor-γ agonist treatment, the rate of depletion of plaque CD68(+) cells was unaffected, but there was a further increase in their expression of antiinflammatory macrophage markers.
  
  
  CONCLUSIONS
  The Reversa mouse is a new model of atherosclerosis regression. After lipid lowering, favorable changes in plaque composition were independent of changes in size. In addition, plaque CD68(+) cells became less inflammatory, an effect enhanced by treatment with pioglitazone.
authors.affiliation: Smilow 8, 522 First Ave, New York, NY 10016, USA.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Feig
authors.forename: Sajesh
authors.initials: S
authors.lastname: Parathath
authors.forename: James X
authors.initials: JX
authors.lastname: Rong
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Mick
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Vengrenyuk
authors.forename: Lisa
authors.initials: L
authors.lastname: Grauer
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Young
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fisher
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods; D005812:Genes, Switch / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D006937:Hypercholesterolemia / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D007249:Inflammation / Q000235:genetics / Q000473:pathology / Q000628:therapy; D008264:Macrophages / Q000145:classification / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008861:Microsomes / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: D002352:Carrier Proteins; C106092:microsomal triglyceride transfer protein