title: Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1.
abstract: Accumulation of foam cells in the neointima represents a key event in atherosclerosis. We previously demonstrated that Tanshinone IIA (Tan), a lipophilic bioactive compound extracted from Salvia miltiorrhiza Bunge, inhibits experimental atherogenesis, yet the detailed mechanisms are not fully understood. In this study, we sought to explore the potential effects of Tan on lipid accumulation in macrophage foam cells and the underlying molecular mechanisms. Our data indicate that Tan treatment reduced the content of macrophages, cholesterol accumulation, and the development of atherosclerotic plaque in apolipoprotein E-deficient mice. In human macrophages, Tan ameliorated oxidized low density lipoporotein (oxLDL)-elicited foam cell formation by inhibiting oxLDL uptake and promoting cholesterol efflux. Mechanistically, Tan markedly reduced the expression of scavenger receptor class A and increased the expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1 in lipid-laden macrophages via activation of the extracellular signal-regulated kinase (ERK)/nuclear factor-erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. Tan treatment induced the phosphorylation and nuclear translocation of Nrf2 and subsequently increased the expression of HO-1, and these effects were abolished by the specific ERK inhibitors, PD98059 and U0126. Moreover, HO-1 small interfering RNA or zinc protoporphyrin (a HO-1 inhibitor) abrogated Tan-mediated suppression of lipid accumulation in macrophages. Our current findings demonstrate that a novel HO-1-dependent mechanism is involved in the regulation of cholesterol balance by Tan.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, Guangdong, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Wang
authors.forename: Erwen
authors.initials: E
authors.lastname: Huang
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.forename: Hong
authors.initials: H
authors.lastname: Li
authors.forename: Jing
authors.initials: J
authors.lastname: Lu
authors.forename: Kunming
authors.initials: K
authors.lastname: Tian
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Little
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shen
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
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; D045784:Abietanes / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D051116:Receptors, Scavenger / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D045784:Abietanes; D008077:Lipoproteins, LDL; D051116:Receptors, Scavenger; D018808:Transcription Factor AP-1; C099252:oxidized low density lipoprotein; C021751:tanshinone; D004247:DNA; D002784:Cholesterol; D051547:Heme Oxygenase-1
keywords: ATP-binding cassette transporter A1/G1; cell signaling; class A scavenger receptor; heme catabolism enzyme