College of Life Science & Bioengineering, Beijing University of Technology, Pingleyuan 100#, District of Chaoyang, Beijing, China.
J Cell Physiol. 2014 Sep;229(9):1193-201. doi: 10.1002/jcp.24552.
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.
Tat 反式激活活性受 NAD(+)依赖的组蛋白去乙酰化酶 Sirtuin1 (SIRT1)调节，将 HIV 转录与细胞的代谢状态联系起来。烟酰胺磷酸核糖转移酶 (Nampt) 是哺乳动物 NAD(+)生物合成的限速酶。Nampt、SIRT1 和 AMPK 通过氧化还原调节途径参与抑制 HIV-1 转录激活。丹参酮 IIA 是丹参根的主要脂溶性单体衍生物，丹参酮 IIA 通过氧化还原信号通路具有多种生物学活性。在这里，我们研究了丹参酮 IIA 对 Tat 诱导的 HIV-1 转录激活及其涉及的氧化还原信号通路的影响。结果表明，丹参酮 IIA 通过上调 Nrf2 表达逆转 Tat 诱导的 TZM-bl 细胞中活性氧 (ROS) 的产生和谷胱甘肽 (GSH) 水平的下调。丹参酮 IIA 逆转了 Tat 诱导的 SIRT1 活性抑制，但不影响 SIRT1 蛋白表达。丹参酮 IIA 以剂量依赖性方式逆转了 Tat 诱导的 TZM-bl 细胞中 Nampt 蛋白表达的抑制和 NAD(+)水平的消耗。丹参酮 IIA 诱导的 Nampt 表达是通过 AMPK 信号通路介导的。丹参酮 IIA 通过 AMPK-Nampt 途径抑制 Tat 诱导的 HIV-1 LTR 转录激活。总之，我们的数据为理解丹参酮 IIA 抑制 Tat 调节转录的分子机制提供了新的见解，表明靶向 AMPK/Nampt/SIRT1 途径可能成为新的抗 HIV-1 药物。
