IMPAIRED AUTOPHAGY IN ARTERIAL FOAM CELL POPULATIONS DURING ATHEROSCLEROSIS

Abstract

<h3>BACKGROUND</h3> 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. <h3>METHODS AND RESULTS</h3> 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. <h3>CONCLUSION</h3> 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. <i>Canadian Institutes of Health Research - Operating Grant, Heart and Stroke Foundation, Ontario</i>