title: Manzamine A, a marine-derived alkaloid, inhibits accumulation of cholesterol ester in macrophages and suppresses hyperlipidemia and atherosclerosis in vivo.
abstract: The formation of foam cells in macrophages plays an essential role in the progression of early atherosclerotic lesions and therefore its prevention is considered to be a promising target for the treatment of atherosclerosis. We found that an extract of the marine sponge Acanthostrongylophora ingens inhibited the foam cell formation induced by acetylated low-density lipoprotein (AcLDL) in human monocyte-derived macrophages, as measured based on the accumulation of cholesterol ester (CE). Bioassay-guided purification of inhibitors from the extract afforded manzamines. Manzamine A was the most potent inhibitor of foam cell formation, and also suppressed CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2. In addition, manzamine A inhibited ACAT activity. Next, we orally administered manzamine A to apolipoprotein E (apoE)-deficient mice for 80 days, and found that total cholesterol, free cholesterol, LDL-cholesterol, and triglyceride levels in serum were significantly reduced and the area of atherosclerotic lesions in the aortic sinus was also substantially diminished. These findings clearly suggest that manzamine A suppresses hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting ACAT and is therefore a promising lead compound in the prevention or treatment of atherosclerosis. Although manzamine A has been reported to show several biological activities, this is the first report of a suppressive effect of manzamine A on atherosclerosis in vivo.
authors.affiliation: Department of Natural Medicines, Graduate School of Pharmaceutical Sciences, Kumamoto University, Oe-honmachi 5-1, Kumamoto 862-0973, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Eguchi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Akinori
authors.initials: A
authors.lastname: Hayashida
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.forename: Hikaru
authors.initials: H
authors.lastname: Kato
authors.forename: Henki
authors.initials: H
authors.lastname: Rotinsulu
authors.forename: Fitje
authors.initials: F
authors.lastname: Losung
authors.forename: Remy E P
authors.initials: RE
authors.lastname: Mangindaan
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: de Voogd
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Sachiko
authors.initials: S
authors.lastname: Tsukamoto
mesh_terms: D000470:Alkaloids / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000517:prevention & control*; D016466:CHO Cells; D002227:Carbazoles / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use*; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000517:prevention & control*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011161:Porifera / Q000737:chemistry; D002785:Sterol O-Acyltransferase / Q000378:metabolism; D000097587:Sterol O-Acyltransferase 2
chemical_list: D000470:Alkaloids; D002227:Carbazoles; D002784:Cholesterol; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C032629:acetyl-LDL; C078290:manzamine A; C493492:sterol O-acyltransferase 1