title: Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia.
abstract: BACKGROUND
  Apoptosis signal-regulating kinase 1 (ASK1), recently identified as one of the mitogen-activated protein kinase kinase kinases, is activated by various extracellular stimuli and involved in a variety of cellular function. Therefore, we first examined the role of ASK1 in vascular remodeling.
  
  
  RESULTS
  We used rat balloon injury model and cultured vascular smooth muscle cells (VSMCs). Arterial ASK1 activity was rapidly and dramatically increased after balloon injury. To specifically inhibit endogenous ASK1 activation, dominant-negative mutant of ASK1 (DN-ASK1) was transfected into rat carotid artery before balloon injury. Gene transfer of DN-ASK1 significantly prevented neointimal formation at 14 days after injury. Bromodeoxyuridine labeling index at 7 days after injury showed that DN-ASK1 remarkably suppressed VSMC proliferation in both the intima and the media. We also examined the role of ASK1 in cultured rat VSMCs. Infection with DN-ASK1 significantly attenuated serum-induced VSMC proliferation and migration. We also compared neointimal formation after cuff placement around the femoral artery between mice deficient in ASK1 (ASK1-/- mice) and wild-type (WT) mice. Neointimal formation at 28 days after cuff injury in ASK1-/- mice was significantly attenuated compared with WT mice. Furthermore, we compared the proliferation and migration of VSMCs isolated from ASK1-/- mice with WT mice. Both proliferation and migration of VSMCs from ASK1-/- mice were significantly attenuated compared with VSMCs from WT mice.
  
  
  CONCLUSIONS
  ASK1 activation plays the key role in vascular intimal hyperplasia. ASK1 may provide the basis for the development of new therapeutic strategy for vascular diseases.
authors.affiliation: Department of Pharmacology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
authors.forename: Yasukatsu
authors.initials: Y
authors.lastname: Izumi
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim
authors.forename: Minoru
authors.initials: M
authors.lastname: Yoshiyama
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yoshida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichijo
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshikawa
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001973:Bromodeoxyuridine; D002339:Carotid Arteries / Q000201:enzymology* / Q000473:pathology; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004789:Enzyme Activation / Q000235:genetics; D018014:Gene Transfer Techniques; D005799:Genes, Dominant; D006965:Hyperplasia / Q000201:enzymology* / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology; D051381:Rats; D017539:Tunica Intima / Q000201:enzymology* / Q000473:pathology; D017540:Tunica Media / Q000201:enzymology / Q000473:pathology
chemical_list: D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; C482859:Map3k5 protein, mouse; D001973:Bromodeoxyuridine