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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.

SUBMITTER: Liu Z

PROVIDER: S-EPMC3886659 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1.

Liu Zhiping Z Wang Jiaojiao J Huang Erwen E Gao Si S Li Hong H Lu Jing J Tian Kunming K Little Peter J PJ Shen Xiaoyan X Xu Suowen S Liu Peiqing P

Journal of lipid research 20131203 2

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 redu ...[more]

PMID: 24302760

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Project description:Background and purposeNAD(P)H: quinone oxidoreductase 1 (NQO1) mediated quinone reduction and subsequent UDP-glucuronosyltransferases (UGTs) catalyzed glucuronidation is the dominant metabolic pathway of tanshinone IIA (TSA), a promising anti-cancer agent. UGTs are positively expressed in various tumor tissues and play an important role in the metabolic elimination of TSA. This study aims to explore the role of UGT1A in determining the intracellular accumulation and the resultant apoptotic effect of TSA.Experimental approachWe examined TSA intracellular accumulation and glucuronidation in HT29 (UGT1A positive) and HCT116 (UGT1A negative) human colon cancer cell lines. We also examined TSA-mediated reactive oxygen species (ROS) production, cytotoxicity and apoptotic effect in HT29 and HCT116 cells to investigate whether UGT1A levels are directly associated with TSA anti-cancer effect. UGT1A siRNA or propofol, a UGT1A9 competitive inhibitor, was used to inhibit UGT1A expression or UGT1A9 activity.Key resultsMultiple UGT1A isoforms are positively expressed in HT29 but not in HCT116 cells. Cellular S9 fractions prepared from HT29 cells exhibit strong glucuronidation activity towards TSA, which can be inhibited by propofol or UGT1A siRNA interference. TSA intracellular accumulation in HT29 cells is much lower than that in HCT116 cells, which correlates with high expression levels of UGT1A in HT29 cells. Consistently, TSA induces less intracellular ROS, cytotoxicity, and apoptotic effect in HT29 cells than those in HCT116 cells. Pretreatment of HT29 cells with UGT1A siRNA or propofol can decrease TSA glucuronidation and simultaneously improve its intracellular accumulation, as well as enhance TSA anti-cancer effect.Conclusions and implicationsUGT1A can compromise TSA cytotoxicity via reducing its intracellular exposure and switching the NQO1-triggered redox cycle to metabolic elimination. Our study may shed a light in understanding the cellular pharmacokinetic and molecular mechanism by which UGTs determine the chemotherapy effects of drugs that are UGTs' substrates.

Project description:Lung adenocarcinoma (LUAD) belongs to a subgroup of non-small cell lung cancer (NSCLC) with an increasing incidence all over the world. Tanshinone IIA (TSA), an active compound of Salvia miltiorrhiza Bunge., has been found to have anti-tumor effects on many tumors, but its anti-LUAD effect and its mechanism have not been reported yet. In this study, bio-information analysis was applied to characterize the potential mechanism of TSA on LUA, biological experiments were used to verify the mechanisms involved. TCGA, Pubchem, SwissTargetPrediction, Venny2.1.0, STRING, DAVID, Cytoscape 3.7.2, Omicshare, GEPIA, RSCBPDB, Chem Draw, AutoDockTools, and PyMOL were utilized for analysis in the bio-information analysis and network pharmacology. Our experiments in vitro focused on the anti-LUAD effects and mechanisms of TSA on LUAD cells (A549 and NCI-H1975 cells) via MTT, plate cloning, Annexin V-FITC and PI dual staining, flow cytometry, and western blot assays. A total of 64 differentially expressed genes (DEGs) of TSA for treatment of LUAD were screened out. Gene ontology and pathway analysis revealed characteristic of the DEGs network. After GEPIA-based DEGs confirmation, 46 genes were considered having significant differences. Further, 10 key DEGs (BTK, HSD11B1, ADAM33, TNNC1, THRA, CCNA2, AURKA, MIF, PLK1, and SORD) were identified as the most likely relevant genes from overall survival analysis. Molecular Docking results showed that CCNA2, CDK2 and PLK1 had the lowest docking energy. MTT and plate cloning assays results showed that TSA inhibited the proliferation of LUAD cells in a concentration-dependent manner. Annexin V-FITC and PI dual staining and flow cytometry assays results told that TSA promoted the apoptosis of the two LUAD cells in different degrees, and induced cycle arrest in the G1/S phase. Western blot results showed that TSA significantly down-regulated the expression of CCNA2, CDK2, AURKA, PLK1, and p-ERK. In summary, TSA could suppress the progression of LUAD by inducing cell apoptosis and arresting cell cycle, and these were done by regulating CCNA2-CDK2 complex and AURKA/PLK1 pathway. These findings are the first to demonstrate the molecular mechanism of TSA in treatment of LUAD combination of network bio-information analysis and biological experiments in vitro.

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Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1.

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Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1.

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