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BACKGROUND
Atherosclerosis is characterized by an accumulation of foam cells within the arterial
wall, resulting from excess cholesterol uptake and buildup of cytosolic lipid droplets
(LDs). Autophagy promotes LD clearance by freeing stored cholesterol for efflux and
has been shown to be atheroprotective. While the role of autophagy in LD catabolism
has been studied in macrophage (Mϕ) -derived foam cells, this has remained unexplored
in vascular smooth muscle cell (VSMC)-derived foam cells that constitute a large fraction
of foam cells within atherosclerotic lesions.
METHODS AND RESULTS
Atherosclerosis was induced in GFP-tagged LC3 autophagy reporter mice by PCSK9-AAV
injection and Western diet feeding. Using flow cytometry of aortic digests, we observed
a significant increase in dysfunctional autophagy of VSMC-derived foam cells during
atherogenesis relative to Mϕ-derived foam cells. Using cell culture models of lipid-loaded
VSMC and Mϕ, we show that autophagy-mediated cholesterol efflux from VSMC foam cells
was poor relative to Mϕ foam cells, and largely occurs when HDL is used as a cholesterol
acceptor, as opposed to apoA-1. We found that this was the result of predominant ABCG1
expression in VSMC foam cells. Using metformin, an autophagy activator, cholesterol
efflux to HDL was significantly increased in VSMC, but not in Mϕ, foam cells.
CONCLUSION
These data demonstrate that VSMC and Mϕ foam cells perform cholesterol efflux by distinct
mechanisms and that autophagy flux is highly impaired in VSMC foam cells, but can
be rescued by pharmacologic means. Further investigation is warranted into specifically
targeting autophagy in VSMC foam cells, the predominant foam cell subtype of advanced
atherosclerotic plaques, to promote reverse cholesterol transport and resolution of
the atherosclerotic plaque.
Canadian Institutes of Health Research - Operating Grant, Heart and Stroke Foundation,
Ontario
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© 2021 Published by Elsevier Inc.
