A Matrix Metalloproteinase Inhibitor, ONO-4817, Suppresses the Development of Aortic Intimal Hyperplasia in Experimental Hyperlipidemic Rabbit

Abstract

SUMMARYInhibition of matrix metalloproteinases (MMPs) would be expected to suppress atherosclerotic neointimal proliferation and thus limit atheromatous plaque progression, but this has not yet been demonstrated morphologically in atherosclerotic intimal hyperplasia induced by cholesterol loading in experimental animals. We therefore investigated whether a broad-spectrum MMP inhibitor (MMPi), ONO-4817, could inhibit the development of intimal hyperplasia in male hyperlipidemic rabbits (n = 6) fed laboratory chow supplemented with 1% cholesterol for 2 months followed by a 1% cholesterol diet plus 100 mg/kg ONO-4817 for another month (Chol + ONO group). Control animals (n = 6) received no ONO-4817. When the aortas were studied both histologically and immunohistochemically, intimal hyperplasia was inhibited in Chol + ONO rabbits. The distribution of macrophages and MMP-12 in the hyperplastic tissue of the Chol + ONO rabbits was limited to the luminal side of the lesions. No such limitation in the distribution of macrophages and MMP-12 was observed in the control group. The distribution of smooth muscle cells in the hyperplastic tissue was not different between the Chol + ONO and control groups. However, the distribution of MMP-2 and MMP-12 was limited to the luminal side of lesions in the Chol + ONO group. This is the first reported evidence that an MMPi can suppress the development of intimal hyperplasia in hyperlipidemic rabbits. (Int Heart J 2007; 48: 369-378)

Montelukast Inhibits Matrix Metalloproteinases Expression in Atherosclerotic Rabbits

“…There is evidence [24][25][26] that increased MMP expression is associated with the development of neointimal lesions after arterial balloon injury in experimental animals. MMP inhibitor can suppress the development of intimal hyperplasia in hyperlipidemic rabbits [27]. However, other studies have demonstrated that doxycycline, a broadspectrum MMP inhibitor, has negligible effects on the development of AngII-induced atherosclerosis in LDL receptor-/-mice [28].…”

Significance of Chymase-Dependent Matrix Metalloproteinase-9 Activation on Indomethacin-Induced Small Intestinal Damages in Rats

“…To study the effect of the MMP inhibitor ONO-4817 against MMP-9 activity and small intestinal damage 24 h after administration of indomethacin, 100 mg/kg ONO-4817 (n ϭ 6) or placebo (n ϭ 6) was administered intraperitoneally 3 h before administration of indomethacin. The dose of ONO-4817 was determined on the basis of previous reports (Okamoto et al, 2007;Takai et al, 2007). The experimental procedures for the animals were conducted in accordance with the guidelines of Osaka Medical College.…”