title: Ablation of MEK kinase 1 suppresses intimal hyperplasia by impairing smooth muscle cell migration and urokinase plasminogen activator expression in a mouse blood-flow cessation model.
abstract: BACKGROUND
  Migration, proliferation, and matrix-degrading protease expression of smooth muscle cells (SMCs) are major features of intimal hyperplasia after vascular injury. Although MEK kinase 1 (MEKK1) has been shown to regulate cell migration and urokinase plasminogen activator (uPA) expression, the precise role of MEKK1 in this process remains unknown.
  
  
  RESULTS
  We triggered a vascular remodeling model by complete ligation of the right common carotid artery in wild-type (WT) and MEKK1-null (MEKK1-/-) mice. The intimal areas 28 days after ligation were significantly decreased in the ligated MEKK1-/- arteries compared with WT arteries (28+/-8 versus 65+/-17 microm2, P<0.05). There were no differences in the ratios of proliferating cell nuclear antigen (PCNA)-positive cells to total cells within the arterial wall between WT and MEKK1-/- arteries. Proliferation capacity also did not differ between WT and MEKK1-/- cultured aortic smooth muscle cells (AoSMCs). In contrast, the number of intimal PCNA-positive cells 7 days after ligation was significantly smaller in MEKK1-/- arteries. Three different migration assays revealed that migration and invasion of MEKK1-/- AoSMCs were markedly impaired. Addition of full-length MEKK1 restored the migration capacity of MEKK1-/- AoSMCs. The number of MEKK1-/- AoSMCs showing lamellipodia formation by epithelial growth factor was significantly smaller compared with those of WT SMCs. Furthermore, uPA expression after ligation was markedly decreased in MEKK1-/- arteries.
  
  
  CONCLUSIONS
  MEKK1 is implicated in vascular remodeling after blood-flow cessation by regulating the migration and uPA expression of SMCs. MEKK1 is a potential target for drug development to prevent vascular remodeling.
authors.affiliation: Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yujiri
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shintani
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nagamachi
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Akio
authors.initials: A
authors.lastname: Hirata
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Hori
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D016893:Carotid Stenosis; D002465:Cell Movement; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006965:Hyperplasia / Q000209:etiology*; D048728:MAP Kinase Kinase Kinase 1 / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000502:physiology; D017539:Tunica Intima / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics*
chemical_list: D048728:MAP Kinase Kinase Kinase 1; D014568:Urokinase-Type Plasminogen Activator