title: Spiromastixones Inhibit Foam Cell Formation via Regulation of Cholesterol Efflux and Uptake in RAW264.7 Macrophages.
abstract: Bioassay-guided evaluation shows that a deep sea-derived fungus, Spiromastix sp. MCCC 3A00308, possesses lipid-lowering activity. Chromatographic separation of a culture broth resulted in the isolation of 15 known depsidone-based analogues, labeled spiromastixones A-O (1-15). Each of these compounds was tested for its ability to inhibit oxidized low-density lipoprotein (oxLDL)-induced foam cell formation in RAW264.7 macrophages. Spiromastixones 6-8 and 12-14 significantly decreased oxLDL-induced lipid over-accumulation, reduced cell surface area, and reduced intracellular cholesterol concentration. Of these compounds, spiromastixones 6 and 14 exerted the strongest inhibitory effects. Spiromastixones 6 and 14 dramatically inhibited cholesterol uptake and stimulated cholesterol efflux to apolipoprotein A1 (ApoA1) and high-density lipoprotein (HDL) in RAW264.7 macrophages. Mechanistic investigation indicated that spiromastixones 6, 7, 12 and 14 significantly up-regulated the mRNA levels of ATP-binding cassette sub-family A1 (ABCA1) and down-regulated those of scavenger receptor CD36, while the transcription of ATP-binding cassette sub-family A1 (ABCG1) and proliferator-activated receptor gamma (PPARγ) were selectively up-regulated by 6 and 14. A transactivation reporter assay revealed that spiromastixones 6 and 14 remarkably enhanced the transcriptional activity of PPARγ. These results suggest that spiromastixones inhibit foam cell formation through upregulation of PPARγ and ABCA1/G1 and downregulation of CD36, indicating that spiromastixones 6 and 14 are promising lead compounds for further development as anti-atherogenic agents.
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. cmwu@implad.ac.cn.
authors.forename: Chongming
authors.initials: C
authors.lastname: Wu
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. cran_lxj@sina.com.
authors.forename: Ran
authors.initials: R
authors.lastname: Chen
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. mingyueliu87@sohu.com.
authors.forename: Mingyue
authors.initials: M
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. liudong_1982@126.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. aixiaoxin9333@sina.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. zhuizhirun@163.com.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. niusi123@126.com.
authors.forename: Siwen
authors.initials: S
authors.lastname: Niu
authors.affiliation: Pharmacology and Toxicology Research Center, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100193, China. pguo@imaplad.ac.cn.
authors.forename: Peng
authors.initials: P
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China. whlin@bjmu.edu.cn.
authors.forename: Wenhan
authors.initials: W
authors.lastname: Lin
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000235:genetics; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001203:Ascomycota / Q000737:chemistry*; D018955:CD36 Antigens / Q000235:genetics; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D053630:Depsides / Q000302:isolation & purification*; D015536:Down-Regulation / Q000187:drug effects; D005487:Foam Cells / Q000187:drug effects* / Q000378:metabolism; D007783:Lactones / Q000302:isolation & purification*; D008074:Lipoproteins / Q000235:genetics; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C487540:ABCG1 protein, mouse; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D053630:Depsides; D007783:Lactones; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D047495:PPAR gamma; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; C000875:depsidone; D002784:Cholesterol
keywords: ABCA1/G1; CD36; PPARγ; Spiromastix sp.; atherosclerosis; foam cell; spiromastixones