Beraprost sodium regulates cell cycle in vascular smooth muscle cells Kip 1 through cAMP signaling by preventing down - regulation of p 27

Objective: Beraprost sodium (BPS), a prostacyclin (PGI ) analogue, has been reported to exhibit beneficial effects on atherosclerosis 2 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 mg/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-29-deoxyuridine (BrdU) incorporation, and Kip1 p27 , a cyclin-dependent kinase (cdk) inhibitor, expression was examined by immunohistochemistry. We also examined the effects of Kip1 BPS on SMC proliferation based on BrdU incorporation and cell cycle analysis. In addition, p27 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 Kip1 after injury, BPS attenuated the proliferation rate of the cells in the media of the coronary artery by 35%, and maintained p27 Kip1 expression, which declined in the control cells. In the cultured proliferating SMC, BPS prevented the down-regulation of p27 . The Kip1 8-bromo-cyclic adenosine monophosphate (8-br-cAMP), a cAMP analogue, had similar actions as BPS in the regulation of p27 . 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 Kip1 inhibitory effect on SMC proliferation by preventing p27 down-regulation.  2001 Elsevier Science B.V. All rights reserved.