Document Detail

Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries.
MedLine Citation:
PMID:  11245651     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: 12-Lipoxygenase (12-LO) products of arachidonate metabolism have growth and chemotactic effects in vascular smooth muscle cells. We have also recently demonstrated increased 12-LO mRNA and protein expression in the neointima of balloon-injured rat carotid arteries. In this study, we evaluated whether 12-LO activation plays a role in neointimal thickening in this rat model by using a specific ribozyme (Rz) directed to rat 12-LO. METHODS AND RESULTS: We designed a chimeric DNA-RNA hammerhead Rz to cleave rat leukocyte-type 12-LO mRNA. This Rz dose-dependently cleaved a 166-nucleotide target 12-LO mRNA substrate in vitro and reduced 12-LO mRNA and protein expression in rat vascular smooth muscle cells. A control mutant Rz (MRz) with a point mutation in the catalytic site was inactive. To test the in vivo efficacy of the 12-LO Rz, the left common carotid arteries of rats were injured with a balloon catheter. The distal half of the injured arteries was treated with Rz or MRz mixed with lipofectin. The proximal half received only lipofectin. Twelve days after injury, intima-to-media ratios were significantly lower in the Rz-treated sections than in untreated sections from the same rat (0.742+/-0.16 versus 1.749+/-0.12, P:<0.001). In contrast, the MRz had no significant effect. CONCLUSIONS: These results indicate the important role of the leukocyte-type 12-LO pathway in restenosis in response to injury.
J L Gu; H Pei; L Thomas; J L Nadler; J J Rossi; L Lanting; R Natarajan
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Circulation     Volume:  103     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2001 Mar 
Date Detail:
Created Date:  2001-03-14     Completed Date:  2001-05-24     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1446-52     Citation Subset:  IM    
Division of Endocrinology and Metabolism, University of Virginia Health Science Center, Charlottesville, VA, 22908, USA.
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MeSH Terms
Analysis of Variance
Angioplasty, Transluminal, Percutaneous Coronary / adverse effects
Arachidonate 12-Lipoxygenase / antagonists & inhibitors,  genetics,  metabolism*
Carotid Artery Diseases / etiology,  prevention & control*
Cell Movement / drug effects
Contrast Media / metabolism
Disease Models, Animal
Fibronectins / metabolism
Fluorescein / metabolism
Hyperplasia / etiology,  prevention & control
Leukocytes / enzymology*
RNA, Catalytic / genetics,  metabolism,  therapeutic use*
RNA, Messenger / drug effects,  metabolism
Rats, Sprague-Dawley
Tunica Intima / pathology*
Grant Support
Reg. No./Substance:
0/Contrast Media; 0/Fibronectins; 0/RNA, Catalytic; 0/RNA, Messenger; 2321-07-5/Fluorescein; EC 12-Lipoxygenase

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