Department of Pharmacy, Integrated Research Institute of Pharmaceutical Sciences, and BK21 PLUS Team for Creative Leader Program for Pharmacomics-based Future Pharmacy, College of Pharmacy, The Catholic University of Korea, Bucheon-si, Korea.
Cardiovasc Ther. 2018 Dec;36(6):e12476. doi: 10.1111/1755-5922.12476. Epub 2018 Nov 29.
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.
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.
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.
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.
尽管他汀类药物和抗血小板药物对动脉粥样硬化具有治疗作用，但单独使用每种药物的单一疗法通常不足以实现患者的治疗目标。我们之前的研究表明，联合他汀类药物/抗血小板药物/抗肿瘤坏死因子（TNF）药物治疗（普伐他汀/沙格雷酯/依那西普）通过抑制 TNF 来减少动脉粥样硬化病变，TNF 是一种促动脉粥样硬化细胞因子，有助于动脉硬化的进展。此外，我们之前的研究表明，联合应用普伐他汀和西洛他唑通过抗 TNF 活性有效减少 TNF 驱动的炎症。因此，在本研究中，我们使用低密度脂蛋白受体（LDLR）敲除（KO）小鼠评估联合普伐他汀和西洛他唑治疗对动脉粥样硬化进展的相加作用。
10 周龄 LDLR KO 小鼠给予高脂肪、高胆固醇饮食，并单独或联合口服普伐他汀和西洛他唑。分析体重、血浆脂质水平以及细胞间黏附分子和炎症细胞因子的水平。此外，用油红 O 染色主动脉和主动脉根部，并对动脉粥样硬化斑块进行定量。
与每种药物单药治疗组相比，联合普伐他汀和西洛他唑治疗组的动脉粥样硬化斑块明显减少。与普伐他汀或西洛他唑治疗组相比，联合治疗组还显示 ICAM-1、MOMA-2、TNF、白细胞介素（IL）-6、甘油三酯、总胆固醇和低密度脂蛋白水平下调，高密度脂蛋白水平上调。
我们的结果表明，普伐他汀和西洛他唑联合治疗通过减少动脉粥样硬化病变进展和改善血管内皮的促炎状态发挥有益作用。这些作用是通过降低黏附分子表达、免疫细胞浸润和细胞因子水平以及对血清胆固醇水平的抗动脉粥样硬化调节来介导的。因此，我们得出结论，与单独使用每种药物相比，联合使用普伐他汀和西洛他唑可能是一种更有效的抗动脉粥样硬化策略。
