Inhibitory effects of cilostazol on proliferation of vascular smooth muscle cells (VSMCs) through suppression of the ERK1/2 pathway.

Aim: The abnormal proliferation of vascular smooth muscle cells (VSMCs) in arterial walls is an important pathogenic factor of vascular disorders such as atherosclerosis and restenosis after angioplasty. During atherogenesis or in response to vessel injury, VSMC proliferation is induced by a number of peptide growth factors released from platelets and VSMCs. Cilostazol is a phosphodiesterase (PDE) 3 inhibitor that increases intracellular cAMP levels and decreases intracellular Ca(2+) levels, inhibiting platelet aggregation and inducing vasodilatation. Cilostazol is also known to have an inhibitory effect on the proliferation of VSMCs, but the anti-proliferative mechanism of cilostazol in VSMCs has not yet been established. In the present study, we investigated whether the anti-proliferative mechanism of cilostazol is associated with the suppression of extracellular signal-regulated kinases (ERK) and phosphatidylinositol 3 kinase (PI3K) signaling pathways.

Methods: To confirm the anti-proliferative effects of cilostazol on VSMCs, VSMCs were induced to proliferate by serum-induced mitogenesis and then were treated with cilostazol for 24 h. And, to investigate whether the anti-proliferative mechanism of cilostazol in VSMCs involves the suppression of the ERK and PI3K pathways, expression of the phosphorylated forms of ERK1/2, Raf, Akt, and glycogen synthase kinase (GSK)-3 were evaluated by western blot.

Results: Cilostazol inhibited VSMC proliferation in a dose-dependent manner. Phosphorylated ERK1/2 and Raf were significantly reduced in a dose-dependent manner, whereas phosphorylated Akt and GSK-3 were not changed.

Conclusion: These results suggest that suppression of the ERK pathway but not the PI3K pathway is an important mechanism in the anti-proliferative effect of cilostazol on VSMCs.