Document Detail


c-Jun regulates vascular smooth muscle cell growth and neointima formation after arterial injury. Inhibition by a novel DNA enzyme targeting c-Jun.
MedLine Citation:
PMID:  11891228     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neointima formation is a characteristic feature of common vascular pathologies, such as atherosclerosis and post-angioplasty restenosis, and involves smooth muscle cell proliferation. Determination of whether the bZIP transcription factor c-Jun plays a direct regulatory role in arterial lesion formation, or indeed in other disease, has been hampered by the lack of a potent and specific pharmacological inhibitor. c-Jun is poorly expressed in the uninjured artery wall and transiently induced following arterial injury in animal models. Here we generated a gene-specific DNAzyme-targeting c-Jun. We show that c-Jun protein is expressed in human atherosclerotic lesions. Dz13, a catalytically active c-Jun DNAzyme, cleaved c-Jun RNA and inhibited inducible c-Jun protein expression in vascular smooth muscle cells. Dz13 blocked vascular smooth muscle cell proliferation with potency exceeding its exact non-catalytic antisense oligodeoxynucleotide equivalent. Moreover, Dz13 abrogated smooth muscle cell repair following scraping injury in vitro and intimal thickening in injured rat carotid arteries in vivo. These studies demonstrate the positive influence on neointima formation by c-Jun and the therapeutic potential of a DNAzyme controlling its expression.
Authors:
Levon M Khachigian; Roger G Fahmy; Guishui Zhang; Yuri V Bobryshev; Anastasia Kaniaros
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-03-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  277     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-06-17     Completed Date:  2002-07-19     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22985-91     Citation Subset:  IM    
Affiliation:
Centre for Thrombosis and Vascular Research, Department of Pathology, University of New South Wales, Sydney, New South Wales 2052, Australia. L.Khachigian@unsw.edu.au
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MeSH Terms
Descriptor/Qualifier:
Animals
Arteries / cytology,  metabolism
Base Sequence
Blotting, Western
Carotid Arteries / metabolism,  pathology
Cell Division
DNA / metabolism*
Gene Expression Regulation, Enzymologic
Humans
Immunohistochemistry
Molecular Sequence Data
Muscle, Smooth / cytology*,  metabolism
Neovascularization, Pathologic*
Protein Binding
Proto-Oncogene Proteins c-jun / metabolism*
RNA / metabolism
Rats
Chemical
Reg. No./Substance:
0/Proto-Oncogene Proteins c-jun; 63231-63-0/RNA; 9007-49-2/DNA

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