Effects of native and myeloperoxidase-modified apolipoprotein a-I on reverse cholesterol transport and atherosclerosis in mice

Arterioscler Thromb Vasc Biol. 2014 Apr;34(4):779-89. doi: 10.1161/ATVBAHA.113.303044. Epub 2014 Jan 9.

Abstract

Objective: Preclinical and clinical studies have shown beneficial effects of infusions of apolipoprotein A-I (ApoA-I) on atherosclerosis. ApoA-I is also a target for myeloperoxidase-mediated oxidation, leading in vitro to a loss of its ability to promote ATP-binding cassette transporter A1-dependent macrophage cholesterol efflux. Therefore, we hypothesized that myeloperoxidase-mediated ApoA-I oxidation would impair its promotion of reverse cholesterol transport in vivo and the beneficial effects on atherosclerotic plaques.

Approach and results: ApoA-I(-/-) or apolipoprotein E-deficient mice were subcutaneously injected with native human ApoA-I, oxidized human ApoA-I (myeloperoxidase/hydrogen peroxide/chloride treated), or carrier. Although early postinjection (8 hours) levels of total ApoA-I in plasma were similar for native versus oxidized human ApoA-I, native ApoA-I primarily resided within the high-density lipoprotein fraction, whereas the majority of oxidized human ApoA-I was highly cross-linked and not high-density lipoprotein particle associated, consistent with impaired ATP-binding cassette transporter A1 interaction. In ApoA-I(-/-) mice, ApoA-I oxidation significantly impaired reverse cholesterol transport in vivo. In advanced aortic root atherosclerotic plaques of apolipoprotein E-deficient mice, native ApoA-I injections led to significant decreases in lipid content, macrophage number, and an increase in collagen content; in contrast, oxidized human ApoA-I failed to mediate these changes. The decrease in plaque macrophages with native ApoA-I was accompanied by significant induction of their chemokine receptor CCR7. Furthermore, only native ApoA-I injections led to a significant reduction of inflammatory M1 and increase in anti-inflammatory M2 macrophage markers in the plaques.

Conclusions: Myeloperoxidase-mediated oxidation renders ApoA-I dysfunctional and unable to (1) promote reverse cholesterol transport, (2) mediate beneficial changes in the composition of atherosclerotic plaques, and (3) pacify the inflammatory status of plaque macrophages.

Keywords: apolipoprotein A-I; atherosclerosis; myeloperoxidase.

MeSH terms

  • ATP Binding Cassette Transporter 1 / metabolism
  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Apolipoprotein A-I / administration & dosage
  • Apolipoprotein A-I / blood*
  • Apolipoprotein A-I / deficiency
  • Apolipoprotein A-I / genetics
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / blood
  • Atherosclerosis / enzymology*
  • Atherosclerosis / genetics
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Biological Transport
  • Cell Line
  • Cholesterol / blood*
  • Cholesterol, HDL / blood
  • Collagen / metabolism
  • Disease Models, Animal
  • Humans
  • Inflammation / blood
  • Inflammation / enzymology*
  • Inflammation / genetics
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Injections, Subcutaneous
  • Macrophages / enzymology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Oxidation-Reduction
  • Peroxidase / metabolism*
  • Plaque, Atherosclerotic
  • Receptors, CCR7 / metabolism

Substances

  • ABCA1 protein, mouse
  • APOA1 protein, human
  • ATP Binding Cassette Transporter 1
  • Apolipoprotein A-I
  • Apolipoproteins E
  • Ccr7 protein, mouse
  • Cholesterol, HDL
  • Receptors, CCR7
  • Collagen
  • Cholesterol
  • Peroxidase