ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice.
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.
Terasaka
Naoki
N
Pharmacology and Molecular Biology Research Laboratories, Sankyo Co Ltd, 1-2-58 Hiromachi, Tokyo, Japan. terasa@shina.sankyo.co.jp
Miyazaki
Atsuhiro
A
Kasanuki
Naomi
N
Ito
Kayoko
K
Ubukata
Naoko
N
Koieyama
Tadashi
T
Kitayama
Ken
K
Tanimoto
Tatsuo
T
Maeda
Naoyuki
N
Inaba
Toshimori
T
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001057:Apolipoproteins E / Q000172:deficiency*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D006801:Humans; D007210:Indoleacetic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000187:drug effects; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
D000924:Anticholesteremic Agents; D001057:Apolipoproteins E; D007210:Indoleacetic Acids; D008055:Lipids; C509302:pactimibe; D002785:Sterol O-Acyltransferase