Document Detail

Activation of apoptosis signal-regulating kinase 1 in injured artery and its critical role in neointimal hyperplasia.
MedLine Citation:
PMID:  14638553     Owner:  NLM     Status:  MEDLINE    
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.
METHODS AND 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.
Yasukatsu Izumi; Shokei Kim; Minoru Yoshiyama; Yasuhiro Izumiya; Kaoru Yoshida; Atsushi Matsuzawa; Hidenori Koyama; Yoshiki Nishizawa; Hidenori Ichijo; Junichi Yoshikawa; Hiroshi Iwao
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2003-11-24
Journal Detail:
Title:  Circulation     Volume:  108     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-05     Completed Date:  2004-01-09     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2812-8     Citation Subset:  AIM; IM    
Department of Pharmacology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.
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MeSH Terms
Adenoviridae / genetics
Carotid Arteries / enzymology*,  pathology
Carotid Artery Injuries / enzymology*,  genetics,  pathology
Cell Division / genetics
Cell Movement / genetics
Cells, Cultured
Disease Models, Animal
Disease Progression
Enzyme Activation / genetics
Gene Transfer Techniques
Genes, Dominant
Hyperplasia / enzymology*,  pathology
MAP Kinase Kinase Kinase 5
MAP Kinase Kinase Kinases / deficiency,  genetics,  metabolism*
Mice, Knockout
Muscle, Smooth, Vascular / cytology,  enzymology
Tunica Intima / enzymology*,  pathology
Tunica Media / enzymology,  pathology
Reg. No./Substance:
59-14-3/Bromodeoxyuridine; EC Kinase Kinase Kinase 5; EC Kinase Kinase Kinases; EC protein, mouse

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