title: Suppressed monocyte recruitment drives macrophage removal from atherosclerotic plaques of Apoe-/- mice during disease regression.
abstract: Experimental models of atherosclerosis suggest that recruitment of monocytes into plaques drives the progression of this chronic inflammatory condition. Cholesterol-lowering therapy leads to plaque stabilization or regression in human atherosclerosis, characterized by reduced macrophage content, but the mechanisms that underlie this reduction are incompletely understood. Mice lacking the gene Apoe (Apoe-/- mice) have high levels of cholesterol and spontaneously develop atherosclerotic lesions. Here, we treated Apoe-/- mice with apoE-encoding adenoviral vectors that induce plaque regression, and investigated whether macrophage removal from plaques during this regression resulted from quantitative alterations in the ability of monocytes to either enter or exit plaques. Within 2 days after apoE complementation, plasma cholesterol was normalized to wild-type levels, and HDL levels were increased 4-fold. Oil red O staining and quantitative mass spectroscopy revealed that esterified cholesterol content was markedly reduced. Plaque macrophage content decreased gradually and was 72% lower than baseline 4 weeks after apoE complementation. Importantly, this reduction in macrophages did not involve migratory egress from plaques or CCR7, a mediator of leukocyte emigration. Instead, marked suppression of monocyte recruitment coupled with a stable rate of apoptosis accounted for loss of plaque macrophages. These data suggest that therapies to inhibit monocyte recruitment to plaques may constitute a more viable strategy to reduce plaque macrophage burden than attempts to promote migratory egress.
authors.affiliation: Department of Gene and Cell Medicine and Immunology Institute, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Stephane
authors.initials: S
authors.lastname: Potteaux
authors.forename: Emmanuel L
authors.initials: EL
authors.lastname: Gautier
authors.forename: Susan B
authors.initials: SB
authors.lastname: Hutchison
authors.forename: Nico
authors.initials: N
authors.lastname: van Rooijen
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Thomas
authors.forename: Mary G
authors.initials: MG
authors.lastname: Sorci-Thomas
authors.forename: Gwendalyn J
authors.initials: GJ
authors.lastname: Randolph
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology*; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D005816:Genetic Complementation Test; D008264:Macrophages / Q000166:cytology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000166:cytology*; D058226:Plaque, Atherosclerotic / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; C515371:Ccr7 protein, mouse; D054400:Receptors, CCR7; D002784:Cholesterol