Abstract 18215: Negative Impact of Myeloperoxidase-modified ApoA-I on Regression of Atherosclerosis
Background: Apolipoprotein A-I (ApoA-I), the major protein of HDL, is a preferred and selective target for myeloperoxidase (MPO) mediated oxidative modification, which leads to a loss of ApoA-I’s ability to promote ABCA-1-dependent cholesterol efflux from macrophages in vitro - a critical process for reverse cholesterol transport. Previous studies have shown regression of atherosclerosis in animals and humans after increasing ApoA-I either genetically or by infusion. We therefore hypothesized that MPO oxidation of ApoA-I would lead to a loss of its ability to mediate regression of atherosclerosis.
Methods: ApoE-/- mice were fed a Western diet for 16 weeks and were then injected (s.c.) four times (every other day) with human ApoA-I, human oxidized ApoA-I (MPO/hydrogen peroxide/chloride oxidized ApoA-I; oxA-I) or PBS. Aortic root sections were used for staining (Oil Red O, CD68, CCR7, monocyte chemoattractant protein-1, mannose receptor, arginase-I) and for laser capture microdissection of CD68+ plaque cells for molecular analysis.
Results: During the short-term treatment period, plaque lipid and CD68+ cell contents were significantly lower (-22% for lipid and -30% for CD68+ cell content) in the ApoA-I injected group compared to the PBS group, while the oxA-I and PBS groups did not differ significantly. The decrease in CD68+ plaque cells was accompanied with an induction (~5 fold) of their chemokine receptor CCR7, previously shown to be a regression factor. There was a significant increase (by 43%) in plaque collagen content in the ApoA-I injected group compared to the oxA-I or PBS group. Furthermore, only non-modified ApoA-I led to a significant reduction of inflammatory M1 markers (MCP-1 and IL-1β) and increase in anti-inflammatory M2 markers (arginase-I and mannose receptor) in the plaques.
Conclusion: ApoA-I's ability to mediate regression of atherosclerosis accompanied with favorable changes in plaque composition and macrophage phenotype is impaired by MPO-mediated oxidation of ApoA-I.
- © 2012 by American Heart Association, Inc.