title: BubR1 insufficiency inhibits neointimal hyperplasia through impaired vascular smooth muscle cell proliferation in mice.
abstract: OBJECTIVE
  BubR1, a cell cycle-related protein, is an essential component of the spindle checkpoint that regulates cell division. Mice with BubR1 expression reduced to 10% of the normal level display a phenotype characterized by progeria; however, the involvement of BubR1 in vascular diseases is still unknown. We generated mice in which BubR1 expression was reduced to 20% (BubR1(L/L) mice) of that in wild-type mice (BubR1(+/+)) to investigate the effects of BubR1 on arterial intimal hyperplasia.
  
  
  RESULTS
  Ten-week-old male BubR1(L/L) and age-matched wild-type littermates (BubR1(+/+)) were used in this study. The left common carotid artery was ligated, and histopathologic examinations were conducted 4 weeks later. Bone marrow transplantation was also performed. Vascular smooth muscle cells (VSMCs) were isolated from the thoracic aorta to examine cell proliferation, migration, and cell cycle progression. Severe neointimal hyperplasia was observed after artery ligation in BubR1(+/+) mice, whereas BubR1(L/L) mice displayed nearly complete inhibition of neointimal hyperplasia. Bone marrow transplantation from all donors did not affect the reconstitution of 3 hematopoietic lineages, and neointimal hyperplasia was still suppressed after bone marrow transplantation from BubR1(+/+) mice to BubR1(L/L) mice. VSMC proliferation was impaired in BubR1(L/L) mice because of delayed entry into the S phase. VSMC migration was unaffected in these BubR1(L/L) mice. p38 mitogen-activated protein kinase-inhibited VSMCs showed low expression of BubR1, and BubR1-inhibited VSMCs showed low expression of p38.
  
  
  CONCLUSIONS
  BubR1 may represent a new target molecule for treating pathological states of vascular remodeling, such as restenosis after angioplasty.
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Kyuragi
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan. takum@surg2.med.kyushu-u.ac.jp.
authors.forename: Takuya
authors.initials: T
authors.lastname: Matsumoto
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Yui
authors.initials: Y
authors.lastname: Harada
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Saito
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Nakatsu
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Teruhisa
authors.initials: T
authors.lastname: Tsuzuki
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
authors.affiliation: From the Department of Surgery and Science, Graduate School of Medical Sciences (R.K., T.M., Y.M.), R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences (Y.H., S.S., Y.Y.), Department of Pathology, Graduate School of Medical Sciences (M.O.), Department of Medical Biophysics and Radiation Biology, Graduate School of Medical Sciences (Y.N., T.T.), and Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences (M.N.), Kyushu University, Fukuoka, Japan.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002340:Carotid Artery Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017536:Carotid Artery, Common / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D018797:Cell Cycle Proteins / Q000172:deficiency* / Q000235:genetics; D002465:Cell Movement; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006965:Hyperplasia; D008026:Ligation; D008297:Male; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D058426:Neointima; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency* / Q000235:genetics; D034622:RNA Interference; D059807:S Phase Cell Cycle Checkpoints; D013997:Time Factors; D014162:Transfection; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cell cycle; neointima; vascular smooth muscle