title: Autophagy is associated with cell fate in the process of macrophage-derived foam cells formation and progress.
abstract: BACKGROUND
  Autophagy 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.
  
  
  RESULTS
  In 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.
  
  
  CONCLUSIONS
  The fate of macrophage FCs was associated with autophagy. Early autophagy enhancement inhibits the formation and progression of macrophage FCs and prevents atherosclerosis.
authors.affiliation: Animal experimental center & Beijing Key Laboratory of Pre-clinical Research and Evaluation for Cardiovascular Implant Materials, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Liu
authors.affiliation: Animal experimental center & Beijing Key Laboratory of Pre-clinical Research and Evaluation for Cardiovascular Implant Materials, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Animal experimental center & Beijing Key Laboratory of Pre-clinical Research and Evaluation for Cardiovascular Implant Materials, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China. cyc_fuwai@sina.com.
authors.forename: Yongchun
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Animal experimental center & Beijing Key Laboratory of Pre-clinical Research and Evaluation for Cardiovascular Implant Materials, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Animal experimental center & Beijing Key Laboratory of Pre-clinical Research and Evaluation for Cardiovascular Implant Materials, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People's Republic of China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001343:Autophagy / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D005487:Foam Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D001057:Apolipoproteins E; D020123:Sirolimus
keywords: ApoE−/− mice; Atherosclerosis; Autophagy; Foam cells; Macrophages