Inhibitory effect of acyl-CoA:cholesterol acyltransferase inhibitor-low density lipoprotein complex on experimental atherosclerosis.

KV-2920 is a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor. To confirm the efficacy of KV-2920-low density lipoprotein (LDL) complex (KV-LDL complex) as a drug-carrier complex on experimental atherosclerosis, we examined its inhibitory effects in vitro and in vivo. LDL was isolated from human plasma and the KV-LDL complex was prepared by incubation in the presence of Celite 545. The complex contained about 800 mol KV-2920 in 1 mol LDL. The cholesterol levels in the serum and aorta of atherogenic mice after 14 weeks of feeding were significantly higher than those of nonatherogenic mice. With the intravenous injection of KV-LDL complex, although the cholesterol levels in the serum were not influenced, the level of cholesterol ester in the aorta of atherogenic mice was significantly reduced. The concentration of cholesterol ester in the macrophages derived from ICR mice was predominantly increased by incubation with LDL for 48 h, this increase was significantly inhibited by incubation with KV-LDL complex. Moreover, the complex also inhibited the increase of cholesterol ester in macrophages following incubation with oxidized LDL. These findings suggest that KV-LDL complex inhibits the foam cell formation of macrophages though action of KV-2920 as an ACAT inhibitor, and prevents the accumulation of cholesterol ester in the aorta of atherogenic mice. Therefore, KV-LDL complex may be useful as a drug-carrier complex in antiatherosclerotic therapy.