Cilostazol enhances macrophage reverse cholesterol transport in vitro and in vivo

Abstract

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, 3H-cholesterol-labeled and acetyl LDL-loaded RAW264.7 cells were intraperitoneally injected into mice and the appearance of the 3H-tracer was monitored in plasma, liver, and feces. Supporting the in vitro data, cilostazol was found to significantly increase 3H-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.