title: 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.
  
  
  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.
authors: Division of Anti-aging, Department of Internal Medicine, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan.
authors: Kazuhiro
authors: K
authors: Nakaya
authors: Makoto
authors: M
authors: Ayaori
authors: Harumi
authors: H
authors: Uto-Kondo
authors: Tetsuya
authors: T
authors: Hisada
authors: Masatsune
authors: M
authors: Ogura
authors: Emi
authors: E
authors: Yakushiji
authors: Shunichi
authors: S
authors: Takiguchi
authors: Yoshio
authors: Y
authors: Terao
authors: Hideki
authors: H
authors: Ozasa
authors: Makoto
authors: M
authors: Sasaki
authors: Tomohiro
authors: T
authors: Komatsu
authors: Fumitaka
authors: F
authors: Ohsuzu
authors: Katsunori
authors: K
authors: Ikewaki
mesh_terms: D001646:Bile / Q000378:metabolism; D001692:Biological Transport; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008954:Models, Biological; D058987:Phosphodiesterase 3 Inhibitors / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D008076:Cholesterol, HDL; D058987:Phosphodiesterase 3 Inhibitors; D013777:Tetrazoles; D002784:Cholesterol; D000242:Cyclic AMP; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D000077407:Cilostazol