Department of Neurosurgery, The Third Xiangya Hospital, Central South University, 410013, Changsha, China.
Medical College, Hunan Normal University, 410000, Changsha, China.
Exp Mol Med. 2022 Sep;54(9):1423-1433. doi: 10.1038/s12276-022-00761-9. Epub 2022 May 2.
Increased focus has been placed on the role of histone deacetylase inhibitors as crucial players in subarachnoid hemorrhage (SAH) progression. Therefore, this study was designed to expand the understanding of SAH by exploring the downstream mechanism of the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) in SAH. The expression of TDP-43 in patients with SAH and rat models of SAH was measured. Then, western blot analysis, immunofluorescence staining, and transmission electron microscope were used to investigate the in vitro effect of TDP-43 on a neuronal cell model of SAH established by oxyhemoglobin treatment. Immunofluorescence staining and coimmunoprecipitation assays were conducted to explore the relationship among histone deacetylase 1 (HDAC1), heat shock protein 70 (HSP70), and TDP-43. Furthermore, the in vivo effect of HDAC1 on SAH was investigated in rat models of SAH established by endovascular perforation. High expression of TDP-43 in the cerebrospinal fluid of patients with SAH and brain tissues of rat models of SAH was observed, and TDP-43 accumulation in the cytoplasm and the formation of inclusion bodies were responsible for axonal damage, abnormal nuclear membrane morphology, and apoptosis in neurons. TDP-43 degradation was promoted by the HDAC1 inhibitor SAHA via the acetylation of HSP70, alleviating SAH, and this effect was verified in vivo in rat models. In conclusion, SAHA relieved axonal damage and neurological dysfunction after SAH via the HSP70 acetylation-induced degradation of TDP-43, highlighting a novel therapeutic target for SAH.
人们越来越关注组蛋白去乙酰化酶抑制剂在蛛网膜下腔出血（SAH）进展中的关键作用。因此，本研究旨在通过探讨组蛋白去乙酰化酶抑制剂 SAHA 在 SAH 中的下游机制来加深对 SAH 的理解。测量了 SAH 患者和 SAH 大鼠模型中 TDP-43 的表达。然后，通过 Western blot 分析、免疫荧光染色和透射电镜观察氧合血红蛋白处理建立的 SAH 神经元细胞模型中 TDP-43 的体外作用。免疫荧光染色和共免疫沉淀实验探讨了 HDAC1、热休克蛋白 70（HSP70）和 TDP-43 之间的关系。此外，通过血管内穿孔建立的 SAH 大鼠模型研究了 HDAC1 对 SAH 的体内作用。观察到 SAH 患者脑脊液和 SAH 大鼠模型脑组织中 TDP-43 高表达，TDP-43 在细胞质中的积累和包含体的形成导致轴突损伤、神经元异常核膜形态和细胞凋亡。HDAC1 抑制剂 SAHA 通过 HSP70 的乙酰化促进 TDP-43 的降解，从而缓解 SAH，这一效应在大鼠模型中得到了体内验证。总之，SAHA 通过 HSP70 乙酰化诱导 TDP-43 降解缓解 SAH 后的轴突损伤和神经功能障碍，为 SAH 提供了一个新的治疗靶点。
