title: Inhibition of ribonucleotide reductase reduces neointimal formation following balloon injury.
abstract: 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.
authors.affiliation: Davis Heart and Lung Research Institute and the Department of Pharmacology, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
authors.forename: Jon C
authors.initials: JC
authors.lastname: Henry
authors.forename: Mary M
authors.initials: MM
authors.lastname: Bonar
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Kearns
authors.forename: Hongmei
authors.initials: H
authors.lastname: Cui
authors.forename: Megan M
authors.initials: MM
authors.lastname: Mutchler
authors.forename: Michael V
authors.initials: MV
authors.lastname: Martin
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Orsini
authors.forename: Howard L
authors.initials: HL
authors.lastname: Elford
authors.forename: Charles A
authors.initials: CA
authors.lastname: Bush
authors.forename: Jay L
authors.initials: JL
authors.lastname: Zweier
authors.forename: Arturo J
authors.initials: AJ
authors.lastname: Cardounel
mesh_terms: D000818:Animals; D002404:Catheterization; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D023903:Coronary Restenosis / Q000473:pathology / Q000517:prevention & control*; D003331:Coronary Vessels / Q000293:injuries*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006877:Hydroxamic Acids / Q000494:pharmacology; D006918:Hydroxyurea / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D012264:Ribonucleotide Reductases; C035419:3,4-dihydroxybenzohydroxamic acid; D006918:Hydroxyurea