title: A matrix metalloproteinase inhibitor, ONO-4817, suppresses the development of aortic intimal hyperplasia in experimental hyperlipidemic rabbit.
abstract: Inhibition 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.
authors.affiliation: First Department of Internal Medicine, National Defense Medical College, Namiki, Tokorozawa, Saitama.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Kimio
authors.initials: K
authors.lastname: Satomura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakayama
authors.forename: Nobukiyo
authors.initials: N
authors.lastname: Tanaka
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Ohsuzu
authors.forename: Junko
authors.initials: J
authors.lastname: Imaki
authors.forename: Masahiko
authors.initials: M
authors.lastname: Yoshioka
authors.forename: Haruo
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D001018:Aortic Diseases / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002791:Cholesterol, Dietary / Q000633:toxicity; D004195:Disease Models, Animal; D006949:Hyperlipidemias / Q000139:chemically induced / Q000150:complications* / Q000201:enzymology; D006965:Hyperplasia / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D010647:Phenyl Ethers / Q000627:therapeutic use*; D011817:Rabbits; D016896:Treatment Outcome; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
chemical_list: D002791:Cholesterol, Dietary; D061965:Matrix Metalloproteinase Inhibitors; C414368:N-hydroxy-5-ethoxymethyloxy-2-methyl-4-(4-phenoxybenzoyl)aminopentanamide; D010647:Phenyl Ethers; D020782:Matrix Metalloproteinases