title: XBP 1-Deficiency Abrogates Neointimal Lesion of Injured Vessels Via Cross Talk With the PDGF Signaling.
abstract: OBJECTIVE
  Smooth muscle cell (SMC) migration and proliferation play an essential role in neointimal formation after vascular injury. In this study, we intended to investigate whether the X-box-binding protein 1 (XBP1) was involved in these processes.
  
  
  RESULTS
  In vivo studies on femoral artery injury models revealed that vascular injury triggered an immediate upregulation of XBP1 expression and splicing in vascular SMCs and that XBP1 deficiency in SMCs significantly abrogated neointimal formation in the injured vessels. In vitro studies indicated that platelet-derived growth factor-BB triggered XBP1 splicing in SMCs via the interaction between platelet-derived growth factor receptor β and the inositol-requiring enzyme 1α. The spliced XBP1 (XBP1s) increased SMC migration via PI3K/Akt activation and proliferation via downregulating calponin h1 (CNN1). XBP1s directed the transcription of mir-1274B that targeted CNN1 mRNA degradation. Proteomic analysis of culture media revealed that XBP1s decreased transforming growth factor (TGF)-β family proteins secretion via transcriptional suppression. TGF-β3 but not TGF-β1 or TGF-β2 attenuated XBP1s-induced CNN1 decrease and SMC proliferation.
  
  
  CONCLUSIONS
  This study demonstrates for the first time that XBP1 is crucial for SMC proliferation via modulating the platelet-derived growth factor/TGF-β pathways, leading to neointimal formation.
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.). lingfang.zeng@kcl.ac.uk qingbo.xu@kcl.ac.uk.
authors: Lingfang
authors: L
authors: Zeng
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Yi
authors: Y
authors: Li
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Juanyao
authors: J
authors: Yang
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Gang
authors: G
authors: Wang
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Andriana
authors: A
authors: Margariti
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Qingzhong
authors: Q
authors: Xiao
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Anna
authors: A
authors: Zampetaki
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Xiaoke
authors: X
authors: Yin
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Manuel
authors: M
authors: Mayr
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Kazutoshi
authors: K
authors: Mori
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Wen
authors: W
authors: Wang
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.).
authors: Yanhua
authors: Y
authors: Hu
authors: From the Cardiovascular Division, King's College London BHF Centre, London, United Kingdom (L.Z., Y.L., J.Y., A.Z., X.Y., M.M., Y.H., Q.X.); Institute of Bioengineering (J.Y., W.W.) and Centre for Clinical Pharmacology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry (Q.X.), Queen Mary University of London, London, United Kingdom; Department of Emergency Medicine, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, China (G.W.); Centre for Experimental Medicine, Queen's University Belfast, Belfast, United Kingdom (A.M.); and Department of Biophysics, Graduate School of Science, Kyoto University, Kyoto, Japan (K.M.). lingfang.zeng@kcl.ac.uk qingbo.xu@kcl.ac.uk.
authors: Qingbo
authors: Q
authors: Xu
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D015536:Down-Regulation; D005263:Femoral Artery / Q000293:injuries; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D058426:Neointima / Q000235:genetics*; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D020239:Receptor Cross-Talk; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D066253:Vascular Remodeling / Q000235:genetics* / Q000502:physiology; D057772:Vascular System Injuries / Q000235:genetics* / Q000503:physiopathology; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D010982:Platelet-Derived Growth Factor; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse
keywords: inositol; microRNAs; proteomics; signal transduction; vascular remodeling