Combination therapy with cilostazol and pravastatin improves antiatherogenic effects in low-density lipoprotein receptor knockout mice

Abstract

Aims: Despite the therapeutic efficacy of statins and antiplatelet agents for atherosclerosis, monotherapy with each drug alone is often insufficient to achieve the patient's therapeutic goals. We previously showed that combined statin/antiplatelet agent/anti-tumor necrosis factor (TNF) agent therapy (pravastatin/sarpogrelate/etanercept) reduces atherosclerotic lesions by inhibiting TNF, an atherogenic cytokine that contributes to the progression of arteriosclerosis. In addition, our previous study showed that combined treatment with pravastatin and cilostazol is effective for reducing TNF-driven inflammation through anti-TNF activity. Therefore, in the present study, we evaluated the additive effects of combined pravastatin and cilostazol therapy on atherosclerotic progression using low-density lipoprotein receptor (LDLR) knockout (KO) mice.

Methods: Ten-week-old LDLR KO mice were fed a high-fat, high-cholesterol diet and orally administered pravastatin and cilostazol alone or in combination. Body weight, plasma lipid levels, and the levels of intracellular adhesion molecules and inflammatory cytokines were analyzed. In addition, aortas and aortic roots were stained with Oil Red O, and atherosclerotic plaques were quantified.

Results: The atherosclerotic plaques in the combined pravastatin and cilostazol treatment groups were significantly reduced compared to those in each drug monotherapy group. The combination therapy group also showed the downregulation of ICAM-1, MOMA-2, TNF, interleukin (IL)-6, triglyceride, total cholesterol, and low-density lipoprotein levels and the upregulation of high-density lipoprotein levels compared to those of the pravastatin- or cilostazol-treated groups.

Conclusions: Our results suggest that combination therapy with pravastatin and cilostazol exerts beneficial effects by decreasing atherosclerotic lesion progression and improving the pro-inflammatory state in the vascular endothelium. These effects are mediated by the reduction in adhesion molecule expression, immune cell infiltration, and cytokine levels and the antiatherosclerotic modulation of serum cholesterol levels. Therefore, we conclude that combined treatment with pravastatin and cilostazol may be a more effective antiatherosclerotic strategy than treatment with either agent alone.

Keywords: LDLR KO mice; atherosclerosis; cilostazol; combination therapy; pravastatin.