title: Granulocyte-macrophage colony-stimulating factor prevents the progression of atherosclerosis via changes in the cellular and extracellular composition of atherosclerotic lesions in watanabe heritable hyperlipidemic rabbits.
abstract: BACKGROUND
  A cytokine network is involved in atherogenesis. This study was conducted to investigate the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the development and composition of atherosclerotic lesions in Watanabe heritable hyperlipidemic (WHHL) rabbits.
  
  
  RESULTS
  GM-CSF (10 microg. kg-1. d-1) was administered to 4-month-old WHHL rabbits (n=9) 5 days a week for 7.5 months, whereas an equal dose of human serum albumin was administered to controls (n=9). The cholesterol levels were not changed significantly by the treatment. Age-matched 4-month-old rabbits (n=7) had atheromatous plaques over 30.7+/-5.7% of the inner surface area of the aortic arch. After treatment, the percentages of surface atheromatous plaques to total aortic arch area were 45.0+/-12.6% in the GM-CSF group and 74.3+/-11.0% in controls (P<0.0001). Histological examination demonstrated that GM-CSF reduced the ratio of intima to media (P<0.01) and cross-sectional areas of atherosclerotic lesions (P<0.0001). Quantitative analysis indicated a marked decrease in the areas of smooth muscle cells (P=0.0001), collagen (P=0.0001), and extracellular lipid deposits (P<0.05) of atheromatous plaques in GM-CSF-treated rabbits compared with controls. The terminal deoxynucleotidyltransferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method and immunohistochemistry were performed to examine the relationship between decreased atherosclerotic lesions and apoptosis. The percentage of TUNEL-positive cells increased in the GM-CSF group (GM-CSF, 24.1+/-4.4% versus control, 11.6+/-3.2%; P<0.0001). GM-CSF enhanced the apoptosis of smooth muscle cells in the shoulder region and the fibrous cap (P<0.0001), suggesting one of the mechanisms for the antiatherogenic effect.
  
  
  CONCLUSIONS
  GM-CSF altered the composition of atherosclerotic lesions and reduced the atherosclerosis in WHHL rabbits.
authors.affiliation: First Department of Internal Medicine, Fukushima Medical University, Fukushima, Japan.
authors.forename: J
authors.initials: J
authors.lastname: Shindo
authors.forename: T
authors.initials: T
authors.lastname: Ishibashi
authors.forename: K
authors.initials: K
authors.lastname: Yokoyama
authors.forename: K
authors.initials: K
authors.lastname: Nakazato
authors.forename: T
authors.initials: T
authors.lastname: Ohwada
authors.forename: M
authors.initials: M
authors.lastname: Shiomi
authors.forename: Y
authors.initials: Y
authors.lastname: Maruyama
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000235:genetics / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D003327:Coronary Disease / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D018450:Disease Progression; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D011817:Rabbits; D011994:Recombinant Proteins; D012709:Serum Albumin; D014280:Triglycerides / Q000097:blood
chemical_list: D008076:Cholesterol, HDL; D011994:Recombinant Proteins; D012709:Serum Albumin; D014280:Triglycerides; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002784:Cholesterol