© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Beraprost sodium regulates cell cycle in vascular smooth muscle cells through cAMP signaling by preventing down-regulation of p27Kip1
First Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
in1041{at}poh.osaka-med.ac.jp
* Corresponding author. Tel.: +81-726-83-1221; fax: +81-726-83-1801
Objective: Beraprost sodium (BPS), a prostacyclin (PGI2) analogue, has been reported to exhibit beneficial effects on atherosclerosis in both human and animal models. To clarify the underlying mechanism, we investigated the effects of BPS on neointimal formation after balloon injury in the canine coronary artery. Furthermore, we determined its anti-atherosclerotic effects in cultured smooth muscle cells (SMCs). Methods: Adult beagle dogs (10–12 kg) were fed on a high-cholesterol diet (10 g/day) and underwent balloon-denudation of the coronary artery. The dogs were divided into two groups: a BPS-treated group (20 µg/kg per day) and a control group. Twenty-eight days after injury, the dogs were killed and the coronary arteries were examined morphometrically. Three days after injury, the proliferative activity in the medial layer of the coronary artery was evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation, and p27Kip1, a cyclin-dependent kinase (cdk) inhibitor, expression was examined by immunohistochemistry. We also examined the effects of BPS on SMC proliferation based on BrdU incorporation and cell cycle analysis. In addition, p27Kip1 regulation was evaluated in primary-cultured SMCs. Results: BPS administration decreased the intima/media ratio (I/M) by 88% in the control group. Three days after injury, BPS attenuated the proliferation rate of the cells in the media of the coronary artery by 35%, and maintained p27Kip1 expression, which declined in the control cells. In the cultured proliferating SMC, BPS prevented the down-regulation of p27Kip1. The 8-bromo-cyclic adenosine monophosphate (8-br-cAMP), a cAMP analogue, had similar actions as BPS in the regulation of p27Kip1. The proliferation of cultured SMC was inhibited in a dose-dependent manner, and cell cycle arrest in the G1 phase was induced by BPS. Conclusions: Our data suggest that BPS inhibits neointimal formation after balloon denudation in the coronary artery through its inhibitory effect on SMC proliferation by preventing p27Kip1 down-regulation.
KEYWORDS Angioplasty; Protein kinases; Prostaglandins; Restenosis; Smooth muscle
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