Angiogenesis inhibitor TNP-470 (AGM-1470) suppresses vascular smooth muscle cell proliferation after balloon injury in rats.
BACKGROUND
Although TNP-470, a synthetic analog of fumagillin, may inhibit vascular intimal hyperplasia, the effects of TNP-470 on smooth muscle cell (SMC) proliferation have not been demonstrated in vivo. The aim of this study was to confirm the effect of TNP-470 on vascular SMC proliferation using a rat carotid artery balloon injury model.


METHODS
Rats were treated with vehicle or with TNP-470 at low dosage (10 mg/kg), medium dosage (20 mg/kg), or high dosage (40 mg/kg). The animals received subcutaneous injections of materials three times a week from the day following balloon injury. All rats were sacrificed at 2 weeks after injury. The ratio of intimal-to-medial cross-sectional areas (I/M ratio) and the PCNA labeling index was calculated for each group. The DNA synthesis of cultured SMCs was also evaluated using [3H]thymidine incorporation assays. Smooth muscle cells were stimulated with basic fibroblast growth factor and TNP-470 (0.01-100 ng/ml) were added.


RESULTS
The inhibition of intimal hyperplasia increased in a dose-dependent manner. TNP-470 also decreased PCNA expression in the neointima and inhibited DNA synthesis of cultured SMCs.


CONCLUSIONS
TNP-470 may be useful in the prevention of vascular intimal hyperplasia.
Ogata
Toshiro
T
Second Department of Surgery, Gunma University School of Medicine, Gunma, Japan.
Kurabayashi
Masahiko
M
Maeno
Toshitaka
T
Sekiguchi
Ken-ichi
K
Hoshino
Yo-ichi
Y
Ishikawa
Susumu
S
Takei
Hiroyuki
H
Nagai
Ryozo
R
Morishita
Yasuo
Y
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D020212:Carotid Artery Injuries / Q000209:etiology*; D002404:Catheterization / Q000009:adverse effects*; D003510:Cyclohexanes; D008297:Male; D023421:Models, Animal; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D051381:Rats; D017208:Rats, Wistar; D012717:Sesquiterpenes / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol