ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice
- 作者：Naoki Terasaka ; Atsuhiro Miyazaki ; Naomi Kasanuki ; Kayoko Ito ; Naoko Ubukata ; Tadashi Koieyama ; Ken Kitayama ; Tatsuo Tanimoto ; Naoyuki Maeda ; Toshimori Inaba
- 关键词：Acyl-CoA ; cholesterol acyltransferase (ACAT) ; Apolipoprotein E-deficient mouse ; Atherosclerosis ; Cholesterol ; Macrophages ; Metalloproteinases
- 刊名：Atherosclerosis
- 出版年：2007
- 期刊代码：28_00219150
- 类别：med
- 出版时间：February 2007
- 卷：190
- 期：2
- 页码：239-247
- 文件大小：589 K
摘要
The objective of the present study was to determine whether a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, pactimibe sulfate (CS-505), could reduce atherosclerotic lesions beyond and independent of the reduction achieved by cholesterol lowering alone from two different types of lesions. (1) Early lesion model. Twelve-week-old apolipoprotein E (apoE)−/− mice were treated with 0.03 or 0.1%(w/w) CS-505, 0.1 or 0.3%avasimibe (CI-1011), or 3%cholestyramine for 12 weeks. Each treatment significantly reduced plasma cholesterol by a similar degree (43–48%). The antiatherosclerotic activity of 0.1%CS-505, however, was more efficacious than the effects of the other treatments (90%versus 40–50%). (2) Advanced lesion model. Twenty-four-week-old apoE−/− mice were treated with 0.03 or 0.1%CS-505 or 0.1%CI-1011 for 12 weeks. CS-505 at 0.1%revealed enhanced lesion reduction compared with 0.1%CI-1011 (77%versus 54%), whereas the plasma cholesterol-lowering effect of 0.1%CS-505 was almost the same as that of 0.1%CI-1011. Furthermore, immunohistochemical analysis demonstrated that CS-505 significantly reduced the number of macrophages and expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13. These data indicate that CS-505 can reduce and stabilize atherosclerotic lesions. This antiatherosclerotic activity is exerted via both cholesterol lowering and direct ACAT inhibition in plaque macrophages.