Probucol and cilostazol exert a combinatorial anti-atherogenic effect in cholesterol-fed rabbits

Abstract

Introduction: Probucol (PB) and cilostazol (CZ) both exhibit anti-atherogenic effects. However, their combinatorial effects are unclear. This study was designed to investigate their combinatorial anti-atherogenic effect in cholesterol-fed rabbits.

Materials and methods: Rabbits were fed a cholesterol diet with PB or CZ alone or both PB and CZ for 16 weeks. The plasma levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, C-reactive protein, superoxide dismutase, malondialdehyde, and nitric oxide (NO) were measured. The aortic atherosclerotic lesions were grossly and microscopically evaluated. Additionally, in vitro experiments were conducted using human umbilical vein endothelial cells.

Results and conclusion: We found that the PB group and the PB+CZ group exhibited a reduction in the lesion areas (70% in the PB+CZ group, 56% in the PB group) compared with the vehicle group. However, although PB alone and PB+CZ led to a reduction in the lesion size, the histological analysis revealed that only PB+CZ significantly decreased the macrophage accumulation and smooth muscle cell proliferation in the lesions compared with the vehicle group. The plasma levels of total cholesterol in the PB+CZ group were decreased compared with the vehicle group, Moreover, PB+CZ exerted obvious anti-oxidant and anti-inflammatory effects. Interestingly, the PB+CZ treatment led to a marked increase in the levels of plasma NO. The in vitro experiments showed that the combinatorial treatment up-regulated the levels of NO and protein S-nitrosylation in endothelial cells treated with oxidized LDL. In summary, these results suggest that PB and CZ exert combinatorial anti-atherogenic effects.

Keywords: Atherosclerosis; C-reactive protein; CRP; CZ; Cilostazol; HCD; HDL; HDL-C; HUVECs; LDL-C; MDA; MФ; NO; PB; Probucol; ROS; Rabbits; S-nitrosylation; SMC; SOD; TC; cilostazol; eNOS; endothelial nitric oxide synthase; high cholesterol diet; high-density lipoprotein cholesterol; high-density lipoproteins; human umbilical vein endothelial cells; low-density lipoprotein cholesterol; macrophages; malondialdehyde; nitric oxide; probucol; reactive oxygen species; smooth muscle cell; superoxide dismutase; total cholesterol.