title: Administration of tyrosyl radical-oxidized HDL inhibits the development of atherosclerosis in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Tyrosyl radical-oxidized HDL (tyrHDL) increases the ability of cells to donate cholesterol to apolipoprotein (apo) A-I for HDL particle formation. We tested whether treatment with tyrHDL raises endogenous HDL cholesterol levels and decreases atherosclerosis development in apoE-deficient mice.
  
  
  RESULTS
  Tyrosyl radical oxidation of mouse HDL induced formation of apoAI-AII heterodimers and enhanced the ability of mouse HDL to deplete cultured fibroblasts of their regulatory pool of cholesterol. 125I-labeled HDL and tyrHDL delivered intraperitoneally were cleared at similar rates from plasma of chow-fed apoE-deficient mice. ApoE-deficient mice injected intraperitoneally twice weekly with 150 microg tyrHDL from age 10 to 18 weeks showed a maximum 2.3-fold increase in endogenous HDL cholesterol levels, which fell toward the end of the treatment period. tyrHDL treatment resulted in 37% less aortic lesion development than in control HDL-treated mice (P<0.001) and 67% less than in saline-injected animals (P<0.001).
  
  
  CONCLUSIONS
  Administration of tyrHDL for 8 weeks resulted in significantly less atherosclerosis development in apoE-deficient mice than injection of HDL or saline. Molecules increasing mobilization of cellular cholesterol to apoAI for HDL particle formation would be expected to decrease atherosclerosis without necessarily causing sustained increases in circulating HDL cholesterol levels.
authors.affiliation: CIHR Group on Molecular and Cell Biology of Lipids and Departments of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Macdonald
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Terry
authors.forename: Luis B
authors.initials: LB
authors.lastname: Agellon
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Nation
authors.forename: Gordon A
authors.initials: GA
authors.lastname: Francis
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000097:blood / Q000517:prevention & control*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood; D005260:Female; D005347:Fibroblasts; D005609:Free Radicals / Q000737:chemistry; D006801:Humans; D008075:Lipoproteins, HDL / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010084:Oxidation-Reduction; D012867:Skin / Q000166:cytology; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D005609:Free Radicals; D008075:Lipoproteins, HDL; D014443:Tyrosine; D002784:Cholesterol; D002785:Sterol O-Acyltransferase