Macrophage apolipoprotein A-I expression protects against atherosclerosis in ApoE-deficient mice and up-regulates ABC transporters

Yan Ru Su, Hiroyuki Ishiguro, Amy S. Major, Dwayne E. Dove, Wenwu Zhang, Alyssa H. Hasty, Vladimir R. Babaev, MacRae F. Linton, Sergio Fazio

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

The antiatherogenic effect of high-density lipoprotein (HDL) and its major protein component apolipoprotein A-I (apoA-I) has been largely attributed to their key roles in reverse cholesterol transport (RCT) and cellular cholesterol efflux. Substantial evidence shows that overexpression of human apoA-I reduces atherosclerosis in animal models. However, it is uncertain whether this protection is due to an increase in plasma HDL level or to a local effect in the artery wall. To test the hypothesis that expression of human apoA-I in macrophages can promote RCT in the artery wall, we used a retroviral construct expressing human apoA-I cDNA (MFG-HAI) to transduce ApoE-/- bone marrow cells and then transplanted these cells into ApoE-/- mice with preexisting atherosclerosis. ApoE-/- mice reconstituted with MFG-HAI marrow had a significant reduction (30%) in atherosclerotic lesions in the proximal aorta compared to control mice that received marrow expressing MFG parental virus. Peritoneal macrophages isolated from MFG-HAI mice showed a four- to fivefold increase in mRNA expression levels of both ATP-binding cassette (ABC) A1 and ABCG1 compared to controls. Our data demonstrate that gene transfer-mediated expression of human apoA-I in macrophages can compensate in part for apoE deficiency and delay the progression of atherosclerotic lesions by stimulating ABC-dependent cholesterol efflux and RCT.

Original languageEnglish (US)
Pages (from-to)576-583
Number of pages8
JournalMolecular Therapy
Volume8
Issue number4
DOIs
StatePublished - Oct 2003
Externally publishedYes

Keywords

  • ABCA1
  • ABCG1
  • Apolipoprotein A-I
  • Apolipoprotein E deficiency
  • Atherosclerosis
  • Bone marrow transplantation
  • Cholesterol efflux
  • Gene therapy
  • Macrophages
  • Retrovirus
  • Reverse cholesterol transport

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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