Abstract 704: Autophagy Activation Promotes Atherosclerosis Regression

Atherosclerosis is characterized by the deposition of cholesterol-rich plaques within the artery wall that are primarily comprised of macrophage and vascular smooth muscle cell (VSMC) foam cells. Atherogenesis is associated with a progressive defect in autophagy, a cell process that promotes cellular cholesterol homeostasis by degrading excess lipids and promoting cholesterol efflux. We recently showed that during atherosclerosis progression, autophagy and cholesterol efflux to HDL was particularly defective in VSMC foam cells as compared to macrophage foam cells. While previous studies have shown that autophagy activation of transcription factor EB by trehalose protects against atherosclerosis, the ability of this therapeutic compound to shrink pre-existing atherosclerotic plaque (atherosclerosis regression ) is unknown. We hypothesized that activating autophagy with trehalose would promote atherosclerosis regression in mice by enhancing macrophage and VSMC reverse cholesterol transport. Mice were injected with a gain of function PCSK9 adeno-associated virus and fed a Western Diet for 16 weeks to promote atherosclerotic plaque progression, followed by a switch to chow diet for 6 weeks to induce plaque regression. During the regression phase, mice received sub-cutaneous injections of saline or trehalose biweekly. Aortic sinuses were evaluated for changes in plaque size and lipid content. Circulating immune cells were quantified by flow cytometry. A switch to chow diet decreased circulating inflammatory and patrolling monocytes as compared to baseline, although no changes between the trehalose and saline treatment groups were observed. Oil Red O staining revealed a decrease in plaque lipid content in trehalose-treated mice as compared to the saline group, suggesting that autophagy activation in mice during atherosclerosis regression promotes favorable plaque remodeling. Our data demonstrates the therapeutic potential of autophagy activation in reducing atherosclerotic plaque burden. Further analysis of autophagy and inflammatory markers to characterize the mechanisms by which trehalose improves atherosclerosis regression is ongoing.