Department of Neurosurgery, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Interventional Treatment Department, Shenzhen Longhua District Central Hospital, Shenzhen, China.
Biomol Biomed. 2024 Jan 3;24(1):61-72. doi: 10.17305/bb.2023.9364.
Intracranial aneurysm (IA) is one of the most challenging cerebrovascular lesions for clinicians. The aim of this study was to investigate the abnormal expression and role of histone deacetylase 9 (HDAC9) in IA-associated injury of vascular endothelial cells (VECs). First, IA tissue and normal arterial tissue were collected and VECs were isolated from IA patients. The expression levels of HDAC9, microRNA (miR)-34a-5p, and vascular endothelial growth factor-A (VEGFA) were determined. Cell viability, proliferation, apoptosis, and migration were assessed by Cell Counting Kit-8 (CCK-8) assay, EdU staining, TUNEL staining, and transwell assay. The binding of miR-34a-5p to VEGFA was analyzed by the dual-luciferase assay, and the accumulation of HDAC9 and lysine histone acetylation at H3 (H3K9, H3K14, and H3K18) on the miR-34a-5p promoter was detected by the chromatin immunoprecipitation assay. The results showed that HDAC9 and VEGFA were increased and miR-34a-5p was decreased in IA tissues and cells. Silencing of HDAC9 inhibited apoptosis and increased viability, proliferation, and migration of VECs, whereas overexpression of HDAC9 exerted the opposite functions. HDAC9 accumulated at the miR-34a-5p promoter to decrease miR-34a-5p expression by reducing H3 locus-specific acetylation and further promoted VEGFA expression. Knockdown of miR-34a-5p or VEGFA overexpression reversed the protective role of HDAC9 silencing in VECs injury. In conclusion, our study suggests that HDAC9 may be a therapeutic target for IA.
颅内动脉瘤（IA）是临床医生面临的最具挑战性的脑血管病变之一。本研究旨在探讨组蛋白去乙酰化酶 9（HDAC9）在与 IA 相关的血管内皮细胞（VEC）损伤中的异常表达和作用。首先，收集 IA 组织和正常动脉组织，并从 IA 患者中分离 VEC。测定 HDAC9、微小 RNA（miR）-34a-5p 和血管内皮生长因子 A（VEGFA）的表达水平。通过细胞计数试剂盒-8（CCK-8）检测、EdU 染色、TUNEL 染色和 Transwell 检测评估细胞活力、增殖、凋亡和迁移。通过双荧光素酶报告基因检测分析 miR-34a-5p 与 VEGFA 的结合，通过染色质免疫沉淀检测 miR-34a-5p 启动子上 HDAC9 和赖氨酸组蛋白 H3（H3K9、H3K14 和 H3K18）的乙酰化积累。结果表明，IA 组织和细胞中 HDAC9 和 VEGFA 增加，miR-34a-5p 减少。沉默 HDAC9 抑制 VEC 凋亡，增加细胞活力、增殖和迁移，而过表达 HDAC9 则发挥相反的作用。HDAC9 在内源 miR-34a-5p 启动子上聚集，通过降低 H3 特定位置的乙酰化来减少 miR-34a-5p 的表达，从而进一步促进 VEGFA 的表达。miR-34a-5p 敲低或 VEGFA 过表达逆转了 HDAC9 沉默对 VEC 损伤的保护作用。总之，本研究表明 HDAC9 可能是 IA 的治疗靶点。
