title: Adeno-associated virus-mediated expression of acid sphingomyelinase decreases atherosclerotic lesion formation in apolipoprotein E(-/-) mice.
abstract: BACKGROUND
  The secretory form of acid sphingomyelinase (ASM) is postulated to play a key role in the retention and aggregation of lipoproteins in the subendothelial space of the arterial wall by converting sphingomyelin in lipoproteins into ceramide. The present study aimed to determine whether the level of circulating ASM activity affects lesion development in mouse model of atherosclerosis.
  
  
  METHODS
  Apolipoprotein E deficient (ApoE(-/-) ) mice were injected intravenously with a recombinant adeno-associated virus (AAV8-ASM) that constitutively expressed high levels of human ASM in liver and plasma.
  
  
  RESULTS
  Plasma sphingomyelin levels were reduced at early but not later time points after the administration of AAV8-ASM despite persistently elevated circulating ASM. No change in serum lipoprotein levels was observed. Thirteen or 17 weeks after the administration of AAV8-ASM, the amount of plaque formation in the aortic sinus was comparable to that of mice treated with a control AAV.
  
  
  CONCLUSIONS
  Unexpectedly, the lesion area of the entire aorta was reduced significantly in the AAV8-ASM virus-treated group. Hepatic expression and secretion of ASM into the circulation did not accelerate or exacerbate, but rather decreased, lesion formation in ApoE(-/-) mice. Thus, plasma ASM activity does not appear to be rate limiting for plaque formation during atherogenesis.
authors.affiliation: Genzyme Corporation, Framingham, MA 01701, USA.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Leger
authors.forename: Leocadia M
authors.initials: LM
authors.lastname: Mosquea
authors.forename: Lingyun
authors.initials: L
authors.lastname: Li
authors.forename: Weilien
authors.initials: W
authors.lastname: Chuang
authors.forename: Joshua
authors.initials: J
authors.lastname: Pacheco
authors.forename: Kristin
authors.initials: K
authors.lastname: Taylor
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Luo
authors.forename: Peter
authors.initials: P
authors.lastname: Piepenhagen
authors.forename: Robin
authors.initials: R
authors.lastname: Ziegler
authors.forename: Rod
authors.initials: R
authors.lastname: Moreland
authors.forename: Akihiro
authors.initials: A
authors.lastname: Urabe
authors.forename: Canwen
authors.initials: C
authors.lastname: Jiang
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
authors.forename: Nelson S
authors.initials: NS
authors.lastname: Yew
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001057:Apolipoproteins E / Q000235:genetics*; D000229:Dependovirus / Q000378:metabolism*; D006652:Histological Techniques; D006801:Humans; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000201:enzymology* / Q000473:pathology; D013108:Sphingomyelin Phosphodiesterase / Q000008:administration & dosage / Q000097:blood / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D008074:Lipoproteins; C112980:acid sphingomyelinase-1; D013108:Sphingomyelin Phosphodiesterase