Masaki Kitahara (1), Tatsuro Kanaki (1), Kyomi Toyoda (1), Chie Miyakoshi
(1), Sakuya Tanaka (1), Taro Tamaki (2) and Yasushi Saito (3)
(1) Shiraoka Research Station of Biological Science, Nissan Chemical
Industries, Ltd., 1470 Shiraoka, Shiraoka-Machi, Minamisaitama, Saitama
349-0294, Japan
(2) Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company,
Ltd., 2-17-43 Noguchicho, Higashimurayama, Tokyo 189-0022, Japan
(3) The Second Department of Internal Medicine, School of Medicine, Chiba
University, 1-8-1 Inohana, Chuo-ku, Chiba, Chiba 260-0856, Japan
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-beta
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.
Keywords: NK-104, Atherosclerosis, Smooth muscle cell, Growth, Extracellular
matrix