title: Adenovirus-mediated gene transfer of human platelet-activating factor-acetylhydrolase prevents injury-induced neointima formation and reduces spontaneous atherosclerosis in apolipoprotein E-deficient mice.
abstract: BACKGROUND
  Atherosclerosis is characterized by an early inflammatory response involving proinflammatory mediators such as platelet-activating factor (PAF)-like phospholipids, which are inactivated by PAF-acetylhydrolase (PAF-AH). The effect of adenovirus-mediated expression of PAF-AH on injury-induced neointima formation and spontaneous atherosclerosis was studied in apolipoprotein E-deficient mice.
  
  
  RESULTS
  Intravenous administration of an adenovirus (5 x 10(8) plaque-forming units) directing liver-specific expression of human PAF-AH resulted in a 3.5-fold increase of plasma PAF-AH activity at day 7 (P<0.001); this was associated with a 2.4- and 2.3-fold decrease in malondialdehyde-modified LDL autoantibodies and the lysophosphatidylcholine/phosphatidylcholine ratio, respectively (P<0.001 for both). Non-HDL and HDL cholesterol levels in PAF-AH-treated mice were similar to those of control virus-treated mice. Seven days after virus injection, endothelial denudation of the common left carotid artery was induced with a guidewire. Neointima formation was assessed 18 days later. PAF-AH gene transfer reduced oxidized lipoproteins by 82% (P<0.001), macrophages by 69% (P=0.006), and smooth muscle cells by 84% (P=0.002) in the arterial wall. This resulted in a 77% reduction (P<0.001) of neointimal area. Six weeks after adenovirus-mediated gene transfer, spontaneous atherosclerotic lesions in the aortic root were analyzed. PAF-AH gene transfer reduced atherosclerotic lesions by 42% (P=0.02) in male mice, whereas a nonsignificant 14% reduction was observed in female mice. Basal and PAF-AH activity after gene transfer were higher in male mice than in female mice (P=0.01 and P=0.04, respectively).
  
  
  CONCLUSIONS
  Gene transfer of PAF-AH inhibited injury-induced neointima formation and spontaneous atherosclerosis in apolipoprotein E-deficient mice. Our data indicate that PAF-AH, by reducing oxidized lipoprotein accumulation, is a potent protective enzyme against atherosclerosis.
authors.affiliation: Center for Molecular and Vascular Biology, Department of Experimental Surgery and Anesthesiology, Katholieke Universiteit Leuven, Leuven, Belgium.
authors.forename: R
authors.initials: R
authors.lastname: Quarck
authors.forename: B
authors.initials: B
authors.lastname: De Geest
authors.forename: D
authors.initials: D
authors.lastname: Stengel
authors.forename: A
authors.initials: A
authors.lastname: Mertens
authors.forename: M
authors.initials: M
authors.lastname: Lox
authors.forename: G
authors.initials: G
authors.lastname: Theilmeier
authors.forename: C
authors.initials: C
authors.lastname: Michiels
authors.forename: M
authors.initials: M
authors.lastname: Raes
authors.forename: H
authors.initials: H
authors.lastname: Bult
authors.forename: D
authors.initials: D
authors.lastname: Collen
authors.forename: P
authors.initials: P
authors.lastname: Van Veldhoven
authors.forename: E
authors.initials: E
authors.lastname: Ninio
authors.forename: P
authors.initials: P
authors.lastname: Holvoet
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001161:Arteriosclerosis / Q000235:genetics / Q000517:prevention & control*; D008076:Cholesterol, HDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000235:genetics; D010741:Phospholipases A / Q000097:blood / Q000235:genetics*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D017539:Tunica Intima / Q000378:metabolism / Q000473:pathology*
chemical_list: D001057:Apolipoproteins E; D008076:Cholesterol, HDL; D015243:Cholesterol, VLDL; D012313:RNA; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase