A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice.
Acyl-coenzyme A:cholesterol O-acyltransferase-1 (ACAT-1) plays an essential role in macrophage foam cell formation and progression of atherosclerosis. We developed a potent and selective ACAT-1 inhibitor, K-604, and tested its effects in apoE-knockout mice. Administration of K-604 to 8-week-old apoE-knockout mice for 12 weeks at a dose of 60 mg/kg/day significantly reduced macrophage-positive area and increased collagen-positive area in atherosclerotic plaques in the aorta without affecting plasma cholesterol levels or lesion areas, indicating direct plaque-modulating effects of K-604 on vascular walls independent of plasma cholesterol levels. Pactimibe, a nonselective inhibitor of ACAT-1 and ACAT-2, reduced plasma cholesterol levels but did not affect macrophage- or collagen-positive areas. The size of macrophages and cholesteryl ester contents in the aorta were reduced by K-604. Exposure of cultured human aortic smooth muscle cells to K-604 resulted in increased procollagen type 1 contents in the culture supernatant and increased procollagen type 1 mRNA levels. Procollagen production was unaffected by pactimibe even at a concentration that inhibited cholesterol esterification to the basal level. Thus, the plaque-modulating effects of K-604 can be explained by stimulation of procollagen production independent of ACAT inhibition in addition to potent inhibition of macrophage ACAT-1.
Yoshinaka
Yasunobu
Y
Tokyo New Drug Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43 Noguchi-cho, Higashimurayama-shi, Tokyo 189-0022, Japan. y-yosink@kowa.co.jp
Shibata
Haruki
H
Kobayashi
Hideyuki
H
Kuriyama
Hiroki
H
Shibuya
Kimiyuki
K
Tanabe
Sohei
S
Watanabe
Takuya
T
Miyazaki
Akira
A
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000166:cytology; D001057:Apolipoproteins E / Q000378:metabolism*; D001562:Benzimidazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism*; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000166:cytology*; D010641:Phenotype
C520671:(2-(4-(2-benzimidazol-2ylthio)ethyl)piperazin-1yl)-N-(2,4-bis(methylthio)-6-methyl-3-pyridyl)acetamide; D001057:Apolipoproteins E; D001562:Benzimidazoles; D008074:Lipoproteins; D003094:Collagen; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase