Abstract
BackgroundAutophagy participates in plaque formation and progression; however, its association with foam cells’ fate is unknown. To investigate autophagy features and its effect on the fate of different-stage macrophage foam cells (FCs). Different-stage FCs were obtained through incubation of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein LDL (oxLDL, 80 μg/mL) for various durations (0–72 h). Autophagy in THP-1 macrophage FCs and in apoE−/− mice was regulated by Rapamycin (80 ug/mL) or 3-MA (10 mM). Lipid droplet accumulation, LC3 I/II, P62 expression level, and autophagic flux were measured. Vascular ultrasound, TUNEL, IHC, and DHE staining were used to detect the artery plaques in apoE−/− mice.ResultsIn early-stage FCs, the amount of autophagosomes gradually increased, and autophagic flux intensity accelerated, but in mid-late stage FCs, autophagic flux was suppressed. For early stage FCs, treatment with autophagy activator rapamycin markedly decreased intracellular lipid content and prevented them from transforming into foam cells, while the autophagy inhibitor 3-MA considerably increased the intracellular lipid-droplet accumulation. During the process of foam cell development, upregulating autophagy not only reduced intracellular lipid-droplet accumulation, but also inhibited cell apoptosis through clearing dysfunctional mitochondria and lowering intracellular ROS level. The in vivo experiments produced consistent results that rapamycin administration in apoE−/− mice reduced the death rate of macrophages and delayed plaque progression.ConclusionsThe fate of macrophage FCs was associated with autophagy. Early autophagy enhancement inhibits the formation and progression of macrophage FCs and prevents atherosclerosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12929-016-0274-z) contains supplementary material, which is available to authorized users.
Highlights
Autophagy participates in plaque formation and progression; its association with foam cells’ fate is unknown
A limited number of clinical studies have shown that autophagic markers are co-localized with macrophages in atherosclerotic plaques, and autophagy is impaired in the advanced stages of atherosclerosis; its deficiency induced lethal accumulation of cholesterol crystals and promoted atherosclerosis [9,10,11]
We investigated the characteristics of autophagy at different stages of the development of THP-1 macrophage (THP-M)-derived foam cells and explored its mechanism of action and effect on middle-late foam cell viability
Summary
Autophagy participates in plaque formation and progression; its association with foam cells’ fate is unknown. To investigate autophagy features and its effect on the fate of different-stage macrophage foam cells (FCs). Different-stage FCs were obtained through incubation of THP-1 macrophages (THP-M) with oxidized low-density lipoprotein LDL (oxLDL, 80 μg/mL) for various durations (0–72 h). Autophagy in THP-1 macrophage FCs and in apoE−/− mice was regulated by Rapamycin (80 ug/mL) or 3-MA (10 mM). LC3 I/II, P62 expression level, and autophagic flux were measured. A limited number of clinical studies have shown that autophagic markers are co-localized with macrophages in atherosclerotic plaques, and autophagy is impaired in the advanced stages of atherosclerosis; its deficiency induced lethal accumulation of cholesterol crystals and promoted atherosclerosis [9,10,11]. Monocytes/macrophages are the predominant cell type expressing autophagy markers in the plaque [12]. There are still some important questions to be elucidated, including changes in autophagy with AS progression, critical time points for correcting dysfunctional autophagy, and the effective regulation of autophagy to achieve a positive effect in inhibiting atheroma progression
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