ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Brain Disease Mechanisms
Volume 18 - 2025 | doi: 10.3389/fnmol.2025.1606973
ACTN2, Regulated by PRDM9, Affects the Growth and Inflammation of Vascular Smooth Muscle Cells by Interacting with PDLIM1 in Intracranial Aneurysms
Provisionally accepted
- Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
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The occurrence of aneurysms is closely related to the growth and inflammatory response of vascular smooth muscle cells (VSMCs). The regulatory mechanism of ACTN2 in intracranial aneurysms (IA) has not yet been fully elucidated.This study aims to reveal the role of the PRDM9-ACTN2-PDLIM1 axis in the progression of aneurysms and its impact on VSMCs.Methods: By integrating GEO datasets (GSE54083, GSE75436) and protein-protein interaction network analysis, ACTN2 was identified as a key gene. Techniques such as shRNA/overexpression, tissue staining, immunofluorescence, ELISA, and Western blot were used to analyze the effects of ACTN2 on VSMC proliferation, apoptosis, inflammation, and the Hippo pathway. The transcriptional regulation of ACTN2 by PRDM9 was validated through ChIP-qPCR, and the role of the PRDM9-H3K4me3-ACTN2 axis was explored using CRISPR-Cas9 experiments. PDLIM1 was screened as an interaction partner of ACTN2, and its role was verified through functional rescue experiments.Results: ACTN2 was significantly downregulated in IA tissues. Its knockdown exacerbated vascular wall damage, VSMC apoptosis, and the release of inflammatory factors by inhibiting the Hippo pathway. PRDM9 promoted ACTN2 transcription through H3K4me3 modification, and its low expression led to ACTN2 suppression, driving VSMC proliferation inhibition and promoting apoptosis and inflammation.PDLIM1 interacted with ACTN2, and its overexpression reversed the effects of ACTN2 knockdown, which depended on the Hippo-YAP signaling pathway.This study reveals that PRDM9 regulates ACTN2 expression through epigenetic modifications and interacts with PDLIM1 to mediate VSMC function and aneurysm progression. The study provides a theoretical basis for clinical intervention.
Keywords: ACTN2, PDLIM1, Prdm9, H3K4Me3, Intracranial aneurysms, VSMCs
Received: 06 Apr 2025; Accepted: 25 Jul 2025.
Copyright: © 2025 Zhang, Zhao, Yu and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Hongyi Liu, Nanjing Brain Hospital Affiliated to Nanjing Medical University, Nanjing, China
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