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Quantification of Atherosclerosis in Mice
06:59

Quantification of Atherosclerosis in Mice

Published on: June 12, 2019

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

Yan Ru Su1, Hiroyuki Ishiguro, Amy S Major

  • 1Atherosclerosis Research Unit, Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6300, USA. yan.ru.su@vanderbilt.edu

Molecular Therapy : the Journal of the American Society of Gene Therapy
|October 8, 2003
PubMed

Insights

Expressing human apolipoprotein A-I (apoA-I) in macrophages reduced atherosclerosis in mice. This suggests local apoA-I expression in artery walls promotes cholesterol efflux and reverse cholesterol transport (RCT).

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Gene Therapy

Background:

  • High-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) exert antiatherogenic effects primarily through reverse cholesterol transport (RCT) and cellular cholesterol efflux.
  • Overexpression of human apoA-I has shown promise in reducing atherosclerosis in animal models, but the precise mechanism (systemic HDL increase vs. local arterial effects) remains unclear.

Purpose of the Study:

  • To investigate whether expressing human apoA-I directly within macrophages in the artery wall can promote RCT and ameliorate atherosclerosis.
  • To determine if macrophage-specific apoA-I expression can compensate for apolipoprotein E (apoE) deficiency in delaying lesion progression.

Main Methods:

  • Utilized a retroviral construct (MFG-HAI) to express human apoA-I cDNA in apolipoprotein E-deficient (ApoE(-/-)) bone marrow cells.
  • Transplanted these genetically modified bone marrow cells into ApoE(-/-) mice with established atherosclerotic lesions.
  • Analyzed atherosclerotic lesion size in the aorta and quantified mRNA expression of ATP-binding cassette transporters (ABCA1 and ABCG1) in peritoneal macrophages.

Main Results:

  • Mice receiving MFG-HAI bone marrow exhibited a significant 30% reduction in atherosclerotic lesions in the proximal aorta compared to control mice.
  • Macrophages from MFG-HAI treated mice displayed a four- to fivefold increase in ABCA1 and ABCG1 mRNA expression.
  • Gene transfer-mediated apoA-I expression in macrophages effectively stimulated ABC transporter-dependent cholesterol efflux.

Conclusions:

  • Local expression of human apoA-I within macrophages can significantly reduce atherosclerosis progression in an apoE-deficient mouse model.
  • Macrophage-derived apoA-I enhances cholesterol efflux and RCT by upregulating ABCA1 and ABCG1 expression.
  • This study highlights the therapeutic potential of targeting macrophage apoA-I for treating atherosclerosis.

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