title: Tanshinone II A inhibits tat-induced HIV-1 transactivation through redox-regulated AMPK/Nampt pathway.
abstract: Tat transactivating activity regulated by NAD(+) -dependent histone deacetylase sirtuin1 (SIRT1) connects HIV transcription with the metabolic state of the cell. Nicotinamide phosphoribosyltransferase (Nampt) is a rate-limiting enzyme in the mammalian NAD(+) biosynthesis. Nampt, SIRT1, and AMPK were involved in inhibiting HIV-1 transactivation through redox-regulated pathway. Tanshinone II A is a main lipid-soluble monomer derivative from the root of Salvia miltiorrhiza (Danshen) and tanshinone II A possess a variety of biological activities through redox signaling pathway. Here we investigated the effect of tanshinone II A on Tat-induced HIV-1 transactivation and the redox signaling pathway involved in it. As the results were shown, tanshinone II A reversed Tat-induced reactive oxygen species (ROS) production and down-regulation of glutathione (GSH) levels in TZM-bl cells through up-regulation of Nrf2 expression. Tanshinone II A reversed Tat-induced inhibition of SIRT1 activity but not SIRT1 protein expression. Tanshinone II A reversed Tat-induced inhibition of Nampt protein expression and depletion of NAD(+) levels in TZM-bl cells in a dose-dependent manner. Tanshinone II A-evoked Nampt expression was mediated by AMPK signaling pathway. Tanshinone II A inhibited Tat-induced HIV-1 LTR transactivation dependent on AMPK-Nampt pathway. Collectively, our data provide new insights into understanding of the molecular mechanisms of tanshinone II A inhibited Tat-regulated transcription, suggesting that targeting AMPK/Nampt/SIRT1 pathway could serve as new anti-HIV-1 agents.
authors.affiliation: College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, China.
authors.forename: Hong-Sheng
authors.initials: HS
authors.lastname: Zhang
authors.forename: Xin-Yu
authors.initials: XY
authors.lastname: Chen
authors.forename: Tong-Chao
authors.initials: TC
authors.lastname: Wu
authors.forename: Feng-Juan
authors.initials: FJ
authors.lastname: Zhang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D045784:Abietanes / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D016325:HIV Long Terminal Repeat / Q000187:drug effects / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D006367:HeLa Cells; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection; D014775:Virus Activation / Q000187:drug effects* / Q000235:genetics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
chemical_list: D045784:Abietanes; D019380:Anti-HIV Agents; D016207:Cytokines; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D054322:tat Gene Products, Human Immunodeficiency Virus; C021751:tanshinone; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D055372:AMP-Activated Protein Kinases; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D005978:Glutathione