title: mTOR enhances foam cell formation by suppressing the autophagy pathway.
abstract: Recently, autophagy has drawn more attention in cardiovascular disease as it has important roles in lipid metabolism. Mammalian target of rapamycin (mTOR) is a key regulator of autophagy; however, its effect on atherosclerosis and the underlying mechanism remains undefined. In this study, an obvious upregulation of mTOR and p-mTOR protein was observed in macrophage-derived foam cells. Blocking mTOR expression with specific small interference RNA (siRNA) dramatically suppressed foam cell formation, accompanied by a decrease of lipid deposition. Further mechanistic analysis indicated that suppressing mTOR expression significantly upregulated autophagic marker LC3 expression and downregulated autophagy substrate p62 levels, indicating that mTOR silencing triggered autophagosome formation. Moreover, blocking mTOR expression obviously accelerated neutral lipid delivery to lysosome and cholesterol efflux from foam cells, implying that mTOR could induce macrophage foam cell formation by suppressing autophagic pathway. Further, mTOR silencing significantly upregulated ULK1 expression, which was accounted for mTOR-induced foam cell formation via autophagic pathway as treatment with ULK1 siRNA dampened LC3-II levels and increased p62 expression, concomitant with lipid accumulation and decreased cholesterol efflux from foam cells. Together, our data provide an insight into how mTOR accelerates the pathological process of atherosclerosis. Accordingly, blocking mTOR levels may be a promising therapeutic agent against atherosclerotic complications.
authors: 1 Department of Emergency Medicine, The Second Affiliated Hospital of Medical College, Xi'an Jiaotong University , Xi'an, People's Republic of China .
authors: Xiaochuang
authors: X
authors: Wang
authors: Lingxia
authors: L
authors: Li
authors: Xiaolin
authors: X
authors: Niu
authors: Xiaoyan
authors: X
authors: Dang
authors: Ping
authors: P
authors: Li
authors: Li
authors: L
authors: Qu
authors: Xiaoju
authors: X
authors: Bi
authors: Yanxia
authors: Y
authors: Gao
authors: Yanfen
authors: Y
authors: Hu
authors: Manxiang
authors: M
authors: Li
authors: Wanhai
authors: W
authors: Qiao
authors: Zhuo
authors: Z
authors: Peng
authors: Longfei
authors: L
authors: Pan
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog; D001391:Azo Compounds; D005487:Foam Cells / Q000166:cytology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008077:Lipoproteins, LDL; D051379:Mice; D008856:Microscopy, Fluorescence; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D001391:Azo Compounds; D047908:Intracellular Signaling Peptides and Proteins; D008077:Lipoproteins, LDL; D034741:RNA, Small Interfering; C099252:oxidized low density lipoprotein; C546842:MTOR protein, human; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; C484754:ULK1 protein, human; C011049:oil red O