title: The inhibition of macrophage foam cell formation by tetrahydroxystilbene glucoside is driven by suppressing vimentin cytoskeleton.
abstract: Macrophage foam cell formation triggered by oxLDL is an important event that occurs during the development of atherosclerosis. 2,3,5,4'-Tetrahydroxystilbene-2-O-β-d-glucoside (TSG) exhibits significant anti-atherosclerotic activity. Herein we used U937 cells induced by PMA and oxLDL in vitro to investigate the inhibitory effects of TSG on U937 differentiation and macrophage foam cell formation. TSG pretreatment markedly inhibited cell differentiation induced by PMA, macrophage apoptosis and foam cell formation induced by oxLDL. The inhibition of vimentin expression and cleavage was involved in these inhibitory effects of TSG. The suppression of vimentin by siRNA in U937 significantly inhibited cell differentiation, apoptosis and foam cell formation. Using inhibitors for TGFβR1 and PI3K, we found that vimentin production in U937 cells is regulated by TGFβ/Smad signaling, but not by PI3K-Akt-mTOR signaling. Meanwhile, TSG pretreatment inhibited both the expression of TGFβ1 and the phosphorylation of Smad2 and Smad3, and TSG suppressed the nuclear translocation of Smad4 induced by PMA and oxLDL. Furthermore, TSG attenuated the induced caspase-3 activation and adhesion molecules levels by PMA and oxLDL. PMA and oxLDL increased the co-localization of vimentin with ICAM-1, which was attenuated by pretreatment with TSG. These results suggest that TSG inhibits macrophage foam cell formation through suppressing vimentin expression and cleavage, adhesion molecules expression and vimentin-ICAM-1 co-localization. The interruption of TGFβ/Smad pathway and caspase-3 activation is responsible for the downregulation of TSG on vimentin expression and degradation, respectively.
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China. Electronic address: yaowenjuan0430@aliyun.com.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Yao
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Qinju
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yang
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Lian
authors.initials: L
authors.lastname: Tang
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Meng
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Xiaole
authors.initials: X
authors.lastname: Xu
authors.affiliation: Key Laboratory of Inflammation and Molecular Drug Target, Department of Pharmacology, School of Pharmacy, Nantong University, 19 QiXiu Road, Nantong 226001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D053938:DNA Fragmentation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D005960:Glucosides / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D020298:U937 Cells; D014746:Vimentin / Q000378:metabolism*
chemical_list: D005960:Glucosides; D008077:Lipoproteins, LDL; D051785:Smad Proteins; D013267:Stilbenes; D053773:Transforming Growth Factor beta1; D014746:Vimentin; C099252:oxidized low density lipoprotein; D018799:Intercellular Adhesion Molecule-1; C093026:2,3,5,4'-tetrahydroxystilbene 2-O-glucopyranoside; D053148:Caspase 3; D013755:Tetradecanoylphorbol Acetate
keywords: Adhesion molecules; Foam cell formation; Tetrahydroxystilbene glucoside; Vimentin