Aberrant expression and regulatory role of histone deacetylase 9 in vascular endothelial cell injury in intracranial aneurysm.

Abstract

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.