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J. Biol. Chem., Vol. 277, Issue 25, 22985-22991, June 21, 2002
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From the Centre for Thrombosis and Vascular Research, Department of
Pathology, University of New South Wales and Department of Haematology,
The Prince of Wales Hospital, Sydney, New South Wales
2052, Australia
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.
c-Jun Regulates Vascular Smooth Muscle Cell Growth and Neointima
Formation after Arterial Injury
INHIBITION BY A NOVEL DNA ENZYME TARGETING c-Jun*
,
*
This work was supported by grants from Johnson and Johnson
Research Pty Limited, National Health and Medical Research Council of
Australia, and New South Wales Department of Health.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Principal Research Fellow of the National Health and Medical
Research Council of Australia. To whom correspondence
should be addressed: Centre for Thrombosis and Vascular Research, Dept. of Pathology, The University of New South Wales, Sydney, NSW 2052, Australia. Tel.: 61-2-9385-2537; Fax: 61-2-9385-1389; E-mail: L.Khachigian@unsw.edu.au.
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