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.