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.
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.
Shiraoka Research Station of Biological Science, Nissan Chemical Industries, Ltd., Minamisaitama, Saitama, Japan.
M
M
Kitahara
T
T
Kanaki
K
K
Toyoda
C
C
Miyakoshi
S
S
Tanaka
T
T
Tamaki
Y
Y
Saito
D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects / Q000502:physiology; D020212:Carotid Artery Injuries; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005353:Fibronectins / Q000096:biosynthesis* / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008055:Lipids / Q000097:blood; D008798:Mevalonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000187:drug effects / Q000378:metabolism; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000503:physiopathology; D017540:Tunica Media / Q000187:drug effects / Q000503:physiopathology
D005353:Fibronectins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011804:Quinolines; D016212:Transforming Growth Factor beta; C015367:mevalonolactone; D004247:DNA; D019821:Simvastatin; D017035:Pravastatin; C108475:pitavastatin; D008798:Mevalonic Acid