Inhibition of ribonucleotide reductase reduces neointimal formation following balloon injury
| Autor: | Arturo J. Cardounel, Jay L. Zweier, Anthony R. Orsini, Megan M. Mutchler, Michael V. Martin, Patrick Kearns, Mary M. Bonar, Jon C. Henry, Charles A. Bush, Howard L. Elford, Hongmei Cui |
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| Rok vydání: | 2005 |
| Předmět: |
Male
Smooth muscle cell migration Cell Ribonucleotide reductase inhibitor Pharmacology Hydroxamic Acids Muscle Smooth Vascular Catheterization Coronary Restenosis Restenosis Cell Movement Ribonucleotide Reductases medicine Animals Hydroxyurea Enzyme Inhibitors Rats Wistar Cell Proliferation Cell growth business.industry medicine.disease Flow Cytometry Coronary Vessels Rats Coronary arteries medicine.anatomical_structure Ribonucleotide reductase Biochemistry Drug delivery Molecular Medicine business |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 314(1) |
| ISSN: | 0022-3565 |
| Popis: | Percutaneous transluminal coronary angioplasty (PTCA) has greatly benefited patients with occluded coronary arteries, but its benefits have been undermined by a high incidence of restenosis. The introduction of coronary stents has significantly improved the short and long term outcome but restenosis still occurs in approximately 15 to 30% of patients within 6 months. Research efforts are now being directed toward combination stenting and drug delivery. Among the therapeutic targets being pursued are agents that can impede smooth muscle cell migration and proliferation, as these processes are critical components of restenosis injury. We propose that inhibiting the conversion of ribonucleotides to deoxyribonucleotides will impede cell proliferation and, as such, limit the degree of restenosis. Therefore, we tested whether the potent ribonucleotide reductase inhibitors Didox (3,4-dihydroxybenzohydraxamic acid) and Imidate (ethyl-3,4,5-hydroxybenzimidate) can limit the neointimal proliferation associated with restenosis using a rat carotid model of balloon dilatation injury. Results demonstrated that both Didox and Imidate significantly reduced intimal thickening, resulting in a 71 and 62% decrease in the intima/media ratio, respectively. Similar efficacy was seen with the commercially available ribonucleotide reductase inhibitor hydroxyurea, demonstrating the importance of this enzyme in vascular remodeling. Results from cell proliferation studies suggest that the mechanism of protection is inhibition of smooth muscle cell (SMC) proliferation. In addition, Didox and Imidate (100 microM) are potent inhibitors of SMC migration, which may also contribute to their vascular protective effects. These results suggest that inhibition of ribonucleotide reductase may provide a potent strategy to prevent post-PTCA restenosis. |
| Databáze: | OpenAIRE |
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