| A DNA enzyme against plasminogen activator inhibitor- type 1 (PAI-1) limits neointima formation after angioplasty in an obese diabetic rodent model. | |
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MedLine Citation:
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PMID: 18091579 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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We investigated whether targeted cleavage of PAI-1 mRNA might prevent post-angioplasty neointima formation in diabetic JCR:LA-cp/cp rats with naturally elevated PAI-1 levels. Catalytic DNA enzymes targeting rat PAI-1 mRNA (PAI-1 DNA enzyme, n = 12) or a random sequence as control (scrambled DNA enzyme, n = 12) were infused at the site of arterial damage. Control animals demonstrated prominent PAI-1 protein expression in the arterial endothelium at 48 hours, and robust neointimal proliferation by two weeks, with 60 +/- 10% mean occlusion of the artery lumen. The neointimal lesion consisted of dense fibrin deposition and numerous proliferating smooth muscle cells, as determined by dual alpha-smooth muscle actin/Ki67 expression. Treatment with PAI-1 DNA enzyme resulted in marked early (48 hour) reduction of endothelial PAI-1 protein expression, which persisted for the next two weeks as well as a two fold reduction of expression of PAI-1 mRNA by RT-PCR at the same time point, (P < 0.05). By two weeks, PAI-1 DNA enzyme treated animals demonstrated significantly reduced levels of fibrin deposition and 5-fold lower levels of proliferating smooth muscle cells at the site of arterial injury compared to controls (P < 0.01), and a 2-fold lower neointima/media ratio (0.67 +/- 0.11 vs 1.39 +/- 0.12) (P < 0.05). Treatment with a catalytic PAI-1 DNA enzyme successfully prevents neointimal proliferation after balloon injury in diabetic animals. |
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Authors:
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Piotr Witkowski; Tetsunori Seki; Guosheng Xiang; Timothy Martens; Hugo Sondermeijer; Fiona See; Govind Bhagat; Michael Schuster; Mark A Hardy; Silviu Itescu |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of cardiovascular pharmacology Volume: 50 ISSN: 0160-2446 ISO Abbreviation: J. Cardiovasc. Pharmacol. Publication Date: 2007 Dec |
Date Detail:
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Created Date: 2007-12-19 Completed Date: 2008-02-27 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7902492 Medline TA: J Cardiovasc Pharmacol Country: United States |
Other Details:
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Languages: eng Pagination: 633-40 Citation Subset: IM |
Affiliation:
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Department of Surgery, Columbia University, College of Surgeons and Physicians, New York, New York, USA. pw2004@columbia.edu |
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| MeSH Terms | |
Descriptor/Qualifier:
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Actins
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analysis Angioplasty, Transluminal, Percutaneous Coronary / methods Animals DNA, Catalytic / administration & dosage, genetics, metabolism* Diabetes Mellitus, Experimental / genetics, metabolism*, physiopathology Disease Models, Animal Fibrin / metabolism Image Interpretation, Computer-Assisted Immunohistochemistry Injections, Intra-Arterial Ki-67 Antigen / analysis Muscle, Smooth / chemistry Obesity / genetics, metabolism*, physiopathology Plasminogen Activator Inhibitor 1 / genetics, metabolism* RNA, Messenger / genetics, metabolism Rats Rats, Inbred Strains Rats, Mutant Strains Reverse Transcriptase Polymerase Chain Reaction Tunica Intima / metabolism, pathology* |
| Chemical | |
Reg. No./Substance:
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0/Actins; 0/DNA, Catalytic; 0/Ki-67 Antigen; 0/Plasminogen Activator Inhibitor 1; 0/RNA, Messenger; 9001-31-4/Fibrin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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