Cilostazol inhibits modified low-density lipoprotein uptake and foam cell formation in mouse peritoneal macrophages.
Internalization of modified low-density lipoprotein (LDL) via macrophage scavenger receptors (e.g. scavenger receptor A and CD36) is thought to play a crucial role in the development of atherosclerotic lesions. Cilostazol, an antiplatelet agent with selective phosphodiesterase 3 inhibitory action, has been reported to ameliorate atherosclerosis in mouse models. However, the effect of cilostazol on modified LDL uptake in macrophages is not known. Thus, we investigated the effect of cilostazol on LDL uptake in mouse peritoneal macrophages (MPM). Cilostazol significantly inhibited oxidized and acetylated LDL uptake in MPM, while cyclic AMP (cAMP)-elevating agents, db-cAMP and other phosphodiesterase 3 or 4 inhibitors, did not inhibit the uptake. Cilostazol did not change cytosolic cAMP levels in MPM, and a protein kinase A (PKA) inhibitor did not influence the inhibitory effects of cilostazol. Cilostazol decreased scavenger receptor A but not CD36 expression. Moreover, cilostazol significantly inhibited foam cell formation, which was represented by an increase in esterified cholesterol content. In conclusion, cilostazol significantly inhibits the uptake of modified LDL and foam cell formation in mouse peritoneal macrophages, and the inhibitory effect of cilostazol can be induced in a cAMP- and PKA-independent manner.
Okutsu
Reiko
R
Free Radical Project, Otsuka Pharmaceutical Co. Ltd., Tokushima, Japan. r_okutsu@research.otsuka.co.jp
Yoshikawa
Tomohiro
T
Nagasawa
Masakazu
M
Hirose
Yoshimi
Y
Takase
Hiromichi
H
Mitani
Kiminobu
K
Okada
Keiko
K
Miyakoda
Goro
G
Yabuuchi
Youichi
Y
D000818:Animals; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004705:Endocytosis / Q000187:drug effects*; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051117:Scavenger Receptors, Class A / Q000187:drug effects / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*
D018955:CD36 Antigens; D002317:Cardiovascular Agents; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D058987:Phosphodiesterase 3 Inhibitors; D058988:Phosphodiesterase 4 Inhibitors; D010726:Phosphodiesterase Inhibitors; D047428:Protein Kinase Inhibitors; D051117:Scavenger Receptors, Class A; D013777:Tetrazoles; C032629:acetyl-LDL; C099252:oxidized low density lipoprotein; D000242:Cyclic AMP; D011493:Protein Kinase C; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D000077407:Cilostazol