Eid Moez, Dzreyan Valentina, Demyanenko Svetlana
Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, Rostov-on-Don, Russia.
Front Physiol. 2022 Apr 27;13:782684. doi: 10.3389/fphys.2022.782684. eCollection 2022.
Sirtuins (SIRTs) are NAD- dependent histone deacetylases. They are involved in a variety of biological pathways and are thought to be a promising target for treating several human disorders. Although evidence is piling up to support the neuroprotective role of SIRTs in ischemic stroke, the role of different sirtuin isoforms needs further investigation. We studied the effects of photothrombotic stroke (PTS) on the expression and localization of sirtuins SIRT1 and SIRT2 in neurons and astrocytes of the penumbra and tested the activity of their selective and non-selective inhibitors. SIRT1 levels significantly decreased in the penumbra cells nuclei and increased in their cytoplasm. This indicated a redistribution of SIRT1 from the nucleus to the cytoplasm after PTS. The expression and intracellular distribution of SIRT1 were also observed in astrocytes. Photothrombotic stroke caused a sharp increase in SIRT2 levels in the cytoplasmic fraction of the penumbra neurons. SIRT2 was not expressed in the penumbra astrocytes. SIRT1 and SIRT2 did not co-localize with TUNEL-positive apoptotic cells. Mice were injected with EX-527, a selective SIRT1 inhibitor; SirReal2, selective SIRT2 inhibitor or salermide, a nonspecific inhibitor of SIRT1 and SIRT2. These inhibitors did not demonstrate any change in the infarction volume or the apoptotic index, compared to the control samples. The studies presented indicate the involvement of these sirtuins in the response of brain cells to ischemia in the first 24 h, but the alterations in their expression and change in the localization of SIRT1 are not related to the regulation of penumbra cell apoptosis in the acute period after PTS.
沉默调节蛋白（SIRTs）是依赖烟酰胺腺嘌呤二核苷酸（NAD）的组蛋白脱乙酰酶。它们参与多种生物学途径，被认为是治疗多种人类疾病的一个有前景的靶点。尽管越来越多的证据支持SIRTs在缺血性中风中的神经保护作用，但不同沉默调节蛋白亚型的作用仍需进一步研究。我们研究了光血栓性中风（PTS）对半暗带神经元和星形胶质细胞中沉默调节蛋白SIRT1和SIRT2表达及定位的影响，并测试了它们的选择性和非选择性抑制剂的活性。PTS后，半暗带细胞核中SIRT1水平显著降低，而细胞质中SIRT1水平升高。这表明PTS后SIRT1从细胞核重新分布到细胞质。在星形胶质细胞中也观察到了SIRT1的表达和细胞内分布。光血栓性中风导致半暗带神经元细胞质部分中SIRT2水平急剧升高。SIRT2在半暗带星形胶质细胞中不表达。SIRT1和SIRT2与TUNEL阳性凋亡细胞不共定位。给小鼠注射选择性SIRT1抑制剂EX - 527、选择性SIRT2抑制剂SirReal2或SIRT1和SIRT2的非特异性抑制剂沙雷米德。与对照样品相比，这些抑制剂在梗死体积或凋亡指数上没有显示出任何变化。所呈现的研究表明这些沉默调节蛋白在最初24小时内参与了脑细胞对缺血的反应，但它们表达的改变以及SIRT1定位的变化与PTS急性期半暗带细胞凋亡的调节无关。
