Department of Neurology, The First Affiliated Hospital of Hainan Medical University, Haikou, China.
Key Laboratory of Brain Science Research & Transformation in Tropical Environment of Hainan Province, Haikou, China.
J Interferon Cytokine Res. 2021 Dec;41(12):439-449. doi: 10.1089/jir.2021.0050.
Ischemic stroke caused by atherosclerosis (AS) poses a serious threat to human life expectancy and quality. With the development of genome-wide association studies, the association of histone deacetylase 9 (HDAC9) expression of atheromatous plaques with ischemic stroke in large arteries has been revealed, but the molecular mechanisms behind this phenomenon have not been elucidated. In this study, we explored the effect of HDAC9 on the P38 mitogen activated protein kinase (P38 MAPK), a classic cellular inflammation-related pathway, by knocking down HDAC9 in vascular endothelial cells with short hairpin RNA (shRNA) and found that HDAC9 may mediate oxidized low density lipoprotein (ox-LDL)-induced inflammatory injury in vascular endothelial cells by regulating the phosphorylation level of P38 MAPK to lead to AS. It can be seen that HDAC9 may be a target to control the formation of atherosclerotic plaques. In follow-up experiments, it was verified that sodium valproate (SVA), as a HDAC9 inhibitor, can indeed antagonize the inflammatory damage of vascular endothelial cells, as well as SB203580, which is a P38 MAPK inhibitor. It proves that SVA may be a potential drug for the prevention and treatment of ischemic stroke.
动脉粥样硬化（AS）引起的缺血性脑卒中严重威胁着人类的预期寿命和生活质量。随着全基因组关联研究的发展，揭示了动脉粥样硬化斑块中组蛋白去乙酰化酶 9（HDAC9）的表达与缺血性脑卒中之间的关联，但这一现象背后的分子机制尚不清楚。在这项研究中，我们通过短发夹 RNA（shRNA）敲低血管内皮细胞中的 HDAC9，探讨了 HDAC9 对 P38 有丝分裂原激活蛋白激酶（P38 MAPK）的影响，P38 MAPK 是经典的细胞炎症相关途径，发现 HDAC9 可能通过调节 P38 MAPK 的磷酸化水平来介导氧化型低密度脂蛋白（ox-LDL）诱导的血管内皮细胞炎症损伤，从而导致 AS。可以看出，HDAC9 可能是控制动脉粥样硬化斑块形成的靶点。在后续实验中，验证了组蛋白去乙酰化酶 9 抑制剂丙戊酸钠（SVA）确实可以拮抗血管内皮细胞的炎症损伤，以及 P38 MAPK 抑制剂 SB203580。这证明 SVA 可能是预防和治疗缺血性脑卒中的潜在药物。
