Abstract 1094: Cilostazol Enhances Macrophage Reverse Cholesterol Transport in vitro and in vivo
Reverse cholesterol transport (RCT) is one of critical mechanisms by which HDL exerts protective effects on the development of atherosclerosis. Cilostazol, an antiplatelet agent with selective phosphodiesterase 3 inhibitory action, has been reported to raise HDL-cholesterol levels in humans and ameliorate atherosclerosis in mice. However, the effect of cilostazol on RCT is not known. Thus, we investigated in vitro as well as in vivo effects of cilostazol on RCT. We observed that treatment with cilostazol increased THP-1 macrophages ABCA1 and ABCG1 expression, pivotal molecules involved in initial step in RCT, in a dose- and time-dependent fashion. These effects translated into enhanced apoA-I- and HDL-mediated cholesterol efflux from the macrophages in a dose-dependent manner. Cilostazol also enhanced ABCA1/G1 gene expression and apoA-I-/HDL-mediated cholesterol efflux from human monocyte-derived macrophages. In contrast, cyclic AMP (cAMP)-elevating agents, db-cAMP and other phospho-diesterase 3 and 4 inhibitors, did not increase apoA-I- and HDL-mediated cholesterol efflux from the macrophages. Cilostazol did not change cytosolic cAMP levels in THP-1 macrophages and a protein kinase A (PKA) inhibitor did not affect cilostazol-induced ABCA1 and ABCG1 expression. To further evaluate RCT in vivo, 3H-cholesterol-labeled RAW264.7 cells were intraperitoneally injected into mice and appearance of 3H-tracer in plasma, liver and feces was monitored. Supporting in vitro data, cilostazol was found to significantly increase the levels of 3H-tracer in plasma as well as feces. In summary, cilostazol promotes apoA-I/HDL-mediated cholesterol efflux in vitro and macrophage RCT in vivo by increasing ABCA1 and ABCG1 expression in a PKA-independent manner, whereby explaining at least in part the cardioprotective effects observed in humans.