Effect of a synthetic matrix metalloproteinase inhibitor (ONO-4817) on neointima formation in hypercholesterolemic hamsters.
Degradation of extracellular matrix (ECM) proteins plays an important role in the development of vascular remodeling. We investigated the alteration of matrix metalloproteinases (MMPs) on the development of neointima formation and the effect of a newly synthesized MMP inhibitor using hypercholesterolemic hamsters. Endothelial injury was achieved by a catheter in the hamster carotid artery. Two weeks after the injury, neointima was detected in all hamsters. Oral administration (twice a day) of ONO-4817 was started 2 hours before injury and continued for the next 2 weeks. The neointimal area, with appearance of maze-like structures, was markedly reduced by 52.4 +/- 8.4% by treatment with ONO-4817 at a dose of 20 mg/kg per day. The treatment by ONO-4817 (20 mg/kg per day) significantly reduced the indexes of histone H1 on day 1, 5, and 10 and the BrdU index of intimal smooth muscle cells on day 5 and 10, but not on day 1. Whereas DNA synthesis was not reduced by ONO-4817, in vitro SMC migration on the other hand was reduced dose dependently. According to the results of western-blotting analysis, the expressions of MMPs were increased 1 week after injury. Especially, MMP-12 was not detected in hamsters without cholesterol diet, but it was much increased after injury in hypercholesterolemic hamsters. Additionally, active form of MMP-12 increased in the injured artery of hypercholesterolemic hamsters. In conclusion, inhibition of MMPs results in the suppression of neointima following vascular injury via both prevention of SMC migration and SMC proliferation of late phase in hypercholesterolemic hamsters. MMP-12 plays an important role on vascular stenosis in hypercholesterolemia and ONO-4817 could be a useful compound for the therapy for this field.
Matsuno
Hiroyuki
H
Department of Pharmacology, Gifu University School, Gifu, Japan. leuven@cc.gifu-u.ac.jp
Ishisaki
Akira
A
Nakajima
Keiichi
K
Kozawa
Osamu
O
D000818:Animals; D020212:Carotid Artery Injuries / Q000378:metabolism / Q000628:therapy*; D002465:Cell Movement; D002478:Cells, Cultured; D006224:Cricetinae; D006937:Hypercholesterolemia / Q000378:metabolism*; D008297:Male; D053508:Matrix Metalloproteinase 12; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology* / Q000627:therapeutic use; D017539:Tunica Intima / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D008666:Metalloendopeptidases; D053508:Matrix Metalloproteinase 12