title: High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation.
abstract: High mobility group box-1 (HMGB1), a potent mediator of inflammation, is known to regulate cellular events through binding to the multiple cell-surface receptors, including RAGE and TLRs. However, the role of TLR4 and details of HMGB1 signaling in vascular smooth muscle cells (VSMCs) migration has not been reported so far. The present study was designed to investigate the hypothesis that HMGB1-induced VSMCs migration is mediated via activation of phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway through TLR4. VSMCs from rat thoracic aorta were studied. HMGB1 (0.1-1000 ng/ml) stimulated VSMCs migration in a dose-dependent manner, with the highest value (about 3.5-fold increase). Incubation of VSMCs with 100 ng/ml caused a rapid increase in PI3K activity and Akt phosphorylation. Migration of VSMCs toward HMGB1 was significantly inhibited by silencing of TLR4 (P < 0.05). We also found pretreated cells with TLR4 siRNA or the PI3 K inhibitor LY294002 could markedly block PI3K/Akt pathway activation and VSMCs migration mediated by HMGB1 (P both <0.05). In conclusion, HMGB1 induces migration of VSMCs through a TLR4-dependent PI3 K/Akt signaling pathway, which suggests a possible molecular mechanism for HMGB1 may contribute to neointima formation in restenosis after vascular damage.
authors.affiliation: Department of Cardiology, The First College of Clinical Medical Sciences, China Three Gorges University, Yichang 443000, Hubei, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Yang
authors.forename: Lihua
authors.initials: L
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Jiawang
authors.initials: J
authors.lastname: Ding
authors.forename: Han
authors.initials: H
authors.lastname: Rong
authors.forename: Wusong
authors.initials: W
authors.lastname: Dong
authors.forename: Xinxin
authors.initials: X
authors.lastname: Li
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002867:Chromones / Q000494:pharmacology; D023903:Coronary Restenosis / Q000473:pathology; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000378:metabolism / Q000494:pharmacology*; D047468:Immunoprecipitation; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D058426:Neointima / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: D002867:Chromones; D017931:DNA Primers; D024243:HMGB1 Protein; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; C104200:Hbp1 protein, rat; C495347:Tlr4 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one