Cilostazol enhances macrophage reverse cholesterol transport in vitro and in vivo
Cilostazol enhances macrophage reverse cholesterol transport in vitro and in vivo
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DOI：
10.1016/j.atherosclerosis.2010.07.024
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发表时间：
2010-11-01
期刊：
影响因子：
5.3
通讯作者：
Ikewaki, Katsunori
中科院分区：
文献类型：
--
作者：
Nakaya, Kazuhiro;Ayaori, Makoto;Ikewaki, Katsunori
目的：最近使用胆固醇酯转移蛋白抑制剂的HDL-胆固醇升高策略的失败突出了抗动脉粥样硬化功能的重要性，而不是HDL的血浆浓度。西洛他唑是一种磷酸二酯酶3的选择性抑制剂，已被广泛用于动脉粥样硬化疾病患者，并已知可增加HDL-胆固醇。然而，目前尚不清楚西洛他唑是否通过促进胆固醇逆向转运（RCT）（HDL的主要抗动脉粥样硬化功能）来增强抗动脉粥样硬化特性。我们观察到用西洛他唑处理THP-1巨噬细胞、人单核细胞衍生的巨噬细胞和RAW264.7细胞以浓度依赖性方式增加ABCA 1和ABCG 1表达，转化为增强的apoA-I和HDL介导的胆固醇从巨噬细胞流出。然而，其他环腺苷酸（cAMP）升高剂没有增加ABCA 1基因表达的THP-1巨噬细胞。西洛他唑没有改变THP-1巨噬细胞和RAW264.7细胞内cAMP水平，蛋白激酶A（PKA）抑制剂没有影响西洛他唑诱导的ABCA 1和ABCG 1表达。为了进一步研究体内RCT，（3）将H-胆固醇标记和乙酰LDL负载的RAW 264.7细胞腹腔内注射到小鼠中，并监测血浆、肝脏和粪便中的（3）H-示踪剂的出现。支持体外数据，发现西洛他唑显著增加（3）血浆和粪便中的H-示踪剂水平。结论：这些发现表明西洛他唑可能通过增加巨噬细胞中ABCA 1/G1表达促进RCT而提供抗动脉粥样硬化作用。(C)2010爱思唯尔爱尔兰有限公司版权所有。
Objective: Recent failure of an HDL-cholesterol raising strategy using a cholesteryl ester transfer protein inhibitor highlights the importance of the anti-atherogenic function rather than plasma concentration of HDL. Cilostazol, a selective inhibitor of phosphodiesterase 3, has been widely used in patients with atherosclerotic diseases and is known to increase HDL-cholesterol. However, it remains unclear whether cilostazol enhances anti-atherogenic properties by promoting reverse cholesterol transport (RCT), a major anti-atherogenic function of HDL.Methods and results: We observed that treatment of THP-1 macrophages, human monocyte-derived macrophages, and RAW264.7 cells with cilostazol increased ABCA1 and ABCG1 expression in a concentration-dependent manner, translating into enhanced apoA-I-and HDL-mediated cholesterol efflux from the macrophages. However, other cyclic AMP (cAMP)-elevating agents did not increase ABCA1 gene expression in THP-1 macrophages. Cilostazol did not change intracellular cAMP levels in THP-1 macrophages and RAW264.7 cells, and a protein kinase A (PKA) inhibitor did not affect cilostazol-induced ABCA1 and ABCG1 expression. To further investigate RCT in vivo, (3)H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were intraperitoneally injected into mice and the appearance of the (3)H-tracer was monitored in plasma, liver, and feces. Supporting the in vitro data, cilostazol was found to significantly increase (3)H-tracer levels in both plasma and feces.Conclusions: These findings indicate that cilostazol might provide anti-atherosclerotic effects by promoting RCT through increased ABCA1/G1 expression in macrophages. (C) 2010 Elsevier Ireland Ltd. All rights reserved.