title: Receptor for advanced glycation end products - membrane type1 matrix metalloproteinase axis regulates tissue factor expression via RhoA and Rac1 activation in high-mobility group box-1 stimulated endothelial cells.
abstract: BACKGROUND
  Atherosclerosis is understood to be a blood vessel inflammation. High-mobility group box-1 (HMGB-1) plays a key role in the systemic inflammation. Tissue factor (TF) is known to lead to inflammation which promotes thrombus formation. Membrane type1 matrix metalloprotease (MT1-MMP) associates with advanced glycation endproducts (AGE) triggered-TF protein expression and phosphorylation of NF-κB. However, it is still unclear about the correlation of MT1-MMP and HMBG-1-mediated TF expression. In this study, we investigated the molecular mechanisms of TF expression in response to HMGB-1 stimulation and the involvement of MT1-MMP in endothelial cells.
  
  
  RESULTS
  Pull-down assays and Western blotting revealed that HMGB-1 induced RhoA/Rac1 activation and NF-kB phosphorylation in cultured human aortic endothelial cells. HMGB-1 increased the activity of MT1-MMP, and inhibition of RAGE or MT1-MMP by siRNA suppressed HMGB-1-induced TF upregulation as well as HMGB-1-triggered RhoA/Rac1 activation and NF-kB phosphorylation.
  
  
  CONCLUSIONS
  The present study showed that RAGE/MT1-MMP axis modified HMBG-1-mediated TF expression through RhoA and Rac1 activation and NF-κB phosphorylation in endothelial cells. These results suggested that MT1-MMP was involved in vascular inflammation and might be a good target for treating atherosclerosis.
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugimoto
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohkawara
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Physiology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.affiliation: Internal Medicine, Ohara General Hospital, Fukushima, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ishibashi
authors.affiliation: Department of Cardiology and Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Yasuchika
authors.initials: Y
authors.lastname: Takeishi
mesh_terms: D050197:Atherosclerosis / Q000473:pathology; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing; D024243:HMGB1 Protein / Q000494:pharmacology*; D006801:Humans; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013925:Thromboplastin / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D024243:HMGB1 Protein; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013925:Thromboplastin; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein