Obovatol from Magnolia obovata inhibits vascular smooth muscle cell proliferation and intimal hyperplasia by inducing p21^Cip1

Abstract 

Aims

Obovatol is isolated from Magnolia obovata leaves and this active component has various pharmacological properties such as anti-oxidant, anti-platelet, anti-fungal and anti-inflammatory activities. In the present study, we investigated the inhibitory effects of obovatol on in vitro vascular smooth muscle cell (VSMC) proliferation and in vivo neointimal formation in a rat carotid artery injury model.

Methods and results

Obovatol (1–5μM) exerted concentration-dependent inhibition on platelet-derived growth factor (PDGF)-BB-induced rat VSMC proliferation, without exhibiting any cellular toxicity or apoptosis, as determined by cell count, [³H]thymidine incorporation and Annexin-V-binding analyses. Treatment with obovatol blocked the cell cycle in G₁ phase by down-regulating the expression of cyclins and CDKs, and selectively up-regulating the expression of p21^Cip1, a well-known CDK inhibitor. Effects of perivascular delivery of obovatol were assessed 14 days after injury. The angiographic mean luminal diameters of the obovatol-treated groups (100μg and 1mg: 0.78±0.06 and 0.77±0.07AU, respectively) were significantly larger than that of the control group (0.58±0.07AU). The obovatol-treated groups (100μg and 1mg: 0.14±0.04 and 0.09±0.03mm², respectively) showed significant reduction in neointimal formation versus the control group (0.17±0.02mm²). Immunohistochemical staining demonstrated strong expression of p21^Cip1 in the neointima of the obovatol-treated groups.

Conclusions

These data suggest that obovatol inhibits VSMC proliferation by perturbing cell cycle progression, possibly due to activation of p21^Cip1 pathway. These results also show that obovatol may have potential as an anti-proliferative agent for the treatment of restenosis and atherosclerosis.

Keywords: Obovatol, Angioplasty, Restenosis, Vascular smooth muscle cell, Carotid arteries, p21^Cip1