NK-104, a Newly Developed HMG-CoA Reductase Inhibitor, Suppresses Neointimal Thickening by Inhibiting Smooth Muscle Cell Growth and Fibronectin Production in Balloon-Injured Rabbit Carotid Artery.

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  • Kitahara Masaki
    Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd.
  • Kanaki Tatsuro
    Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd.
  • Toyoda Kyomi
    Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd.
  • Miyakoshi Chie
    Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd.
  • Tanaka Sakuya
    Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd.
  • Tamaki Taro
    Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd.
  • Saito Yasushi
    The Second Department of Internal Medicine, School of Medicine, Chiba University

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  • NK-104 a Newly Developed HMG-CoA Reduct

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Abstract

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been reported to suppress smooth muscle cell growth and arterial neointimal thickening. In this study, to elucidate the potency and mechanisms of NK-104 ((+)-monocalcium bis｛(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate｝, CAS 147526-32-7) in neointimal thickening, the effect of NK-104 on the neointimal thickening, Br-dU-labeled cell number and extracellular matrix immunohistochemistry were examined in balloon-injured rabbit carotid artery. NK-104 suppressed the neointimal thickening dose-dependently, and the suppression was 69.5% at 1.0 mg/kg. NK-104 suppressed the intimal total and Br-dU-labeled cell number. Fibronectin and type I collagen were observed in 81% and 38% of the total intimal area in the control arteries, respectively, and the areas occupied by fibronectin and type I collagen were significantly decreased by 1.0 mg/kg NK-104 to 39% and 22%, respectively. The decrease in fibronectin per cell was more potently demonstrated. Aortic total and activated TGF-β contents that were markedly increased in the injured artery were increased further by NK-104. NK-104 concentration-dependently suppressed fibronectin content of the basement lesion in rabbit primary cultured smooth muscle cells. These findings suggest that NK-104 suppresses balloon-injury-induced neointimal thickening through inhibition of intimal smooth muscle cell growth and extracellular matrix accumulation.

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