Gene transfer of wild-type apoA-I and apoA-I Milano reduce atherosclerosis to a similar extent

Cardiovasc Diabetol. 2007 May 2;6:15. doi: 10.1186/1475-2840-6-15.

Abstract

Background: The atheroprotective effects of systemic delivery of either apolipoprotein A-I (wtApoA-I) or the naturally occurring mutant ApoA-I Milano (ApoA-IM) have been established in animal and human trials, but direct comparison studies evaluating the phenotype of ApoA-I or ApoAI-Milano knock-in mice or bone marrow transplantated animals with selectively ApoA-I or ApoAI-Milano transduced macrophages give conflicting results regarding the superior performance of either one. We therefore sought to compare the two forms of apoA-I using liver-directed somatic gene transfer in hypercholesterinemic mice--a model which is most adequately mimicking the clinical setting.

Methods and results: Vectors based on AAV serotype 8 (AAV2.8) encoding wtApoA-I, ApoA-IM or green fluorescent protein (GFP) as control were constructed. LDL receptor deficient mice were fed a Western diet. After 8 weeks the AAV vectors were injected, and 6 weeks later atherosclerotic lesion size was determined by aortic en face analysis. Expression of wtApoA-I reduced progression of atherosclerosis by 32% compared with control (p = 0.02) and of ApoA-IM by 24% (p = 0.04). There was no significant difference between the two forms of ApoA-I in inhibiting atherosclerosis progression.

Conclusion: Liver-directed AAV2.8-mediated gene transfer of wtApoA-I and ApoA-IM each significantly reduced atherosclerosis progression to a similar extent.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics*
  • Atherosclerosis / genetics*
  • Atherosclerosis / metabolism*
  • Atherosclerosis / prevention & control
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Humans
  • Hypercholesterolemia / genetics
  • Hypercholesterolemia / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Mutation
  • Receptors, LDL / deficiency
  • Receptors, LDL / genetics
  • Transduction, Genetic* / methods

Substances

  • Apolipoprotein A-I
  • Receptors, LDL