Carvastatin suppresses intimal thickening of rabbit carotid artery after balloon catheter injury probably through the inhibition of vascular smooth muscle cell proliferation and migration.
In order to test whether a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor has an anti-atherogenic activity, the effects of carvastatin, a newly developed potent inhibitor, and pravastatin were examined on the intimal thickening of the artery after the endothelial denudation induced by balloon catheter injury. Rabbits were divided into four groups; control, pravastatin-treated (20 mg kg(-1) day(-1)) and two of carvastatin-treated groups (10 or 20 mg kg(-1) day(-1)). Two weeks after balloon catheter injury, the areas of intima and media of the injured carotid arteries were determined, and the ratios of intima to media (I/M) were calculated as an index of intimal thickening. Average I/M ratios of the injured artery were 0.42+/-0.05 for control, 0.49+/-0.07 for pravastatin, 0.19+/-0.03 (10 mg kg(-1) day(-1)) and 0.20+/-0.04 (20 mg kg(-1) day(-1)) for carvastatin-treated rabbits, respectively. Thus, carvastatin reduced I/M ratio of the injured artery to approximately half versus control, but pravastatin failed to suppress the intimal thickening. For in vitro study, vascular smooth muscle cells (SMC) from rabbit aorta were explanted, then cultured, and the effects of carvastatin on SMC migration and SMC proliferation were also examined. Carvastatin inhibited dose-dependently SMC migration and SMC proliferation with IC50 values of 0.5 microM and 1 microM, respectively. These inhibitory effects of carvastatin were cancelled by the coexistence of mevalonate, a metabolite of cholesterol synthesis. Our results suggest that carvastatin may be useful in rabbits as an anti-atherogenic drug by means of the inhibition of SMC migaration or SMC proliferation.
The Second Department of Internal Medicine, School of Medicine, Chiba University, Japan. komukai@yb3.so-net.ne.jp
M
M
Komukai
Y S
YS
Wajima
J
J
Tashiro
M
M
Shinomiya
Y
Y
Saito
N
N
Morisaki
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001161:Arteriosclerosis / Q000188:drug therapy / Q000473:pathology; D000077214:Becaplermin; D006528:Carcinoma, Hepatocellular; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D008078:Cholesterol, LDL / Q000096:biosynthesis; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017035:Pravastatin / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D011973:Receptors, LDL / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D017539:Tunica Intima / Q000187:drug effects
C120872:1,2,3,4,4a,7,8,8a-octahydro-4,4a-methano-7-methyl-8-(2-(2,4-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-1-naphthyl 2-methylbutanoate; D000925:Anticoagulants; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009281:Naphthalenes; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011714:Pyrans; D011973:Receptors, LDL; D000077214:Becaplermin; D017035:Pravastatin; D008798:Mevalonic Acid