Zhou Han, Wang Chao, Wang Wentao, Guo Pin, Xu Yifan, Cui Zhenwen, Li Xiaolu, Li Shifang, Feng Yugong, Yu Tao
Department of Neurosurgery, Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China.
Department of Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People's Republic of China.
Antioxid Redox Signal. 2025 Sep 23. doi: 10.1177/15230864251380271.
Intracranial aneurysm (IA) is a critical cerebrovascular disorder strongly linked to phenotypic switching and apoptosis of vascular smooth muscle cells (VSMCs). This study aimed to investigate the role of circGNAQ in IA development and elucidate its underlying molecular mechanisms. Reverse transcription-quantitative polymerase chain reaction and fluorescence in situ hybridization revealed significant upregulation of circGNAQ in IA tissues, predominantly localized within VSMCs. In vitro, circGNAQ knockdown attenuated hydrogen peroxide-induced VSMC phenotypic switching and apoptosis, whereas circGNAQ overexpression aggravated these pathological processes. RNA pull-down and mass spectrometry demonstrated that circGNAQ specifically binds to serine/arginine-rich splicing factor 1 (SRSF1), promoting its ubiquitination and degradation, thereby destabilizing SRSF1. Cotransfection assays confirmed that SRSF1 functions as a downstream mediator of circGNAQ in regulating VSMC phenotypic switching and apoptosis. In vivo, circGNAQ knockdown significantly suppressed IA formation in a murine model by inhibiting VSMC phenotypic switching and apoptosis. This study identifies circGNAQ as a novel regulator of VSMC phenotypic switching and apoptosis through targeting SRSF1. The findings highlight circGNAQ as a potential therapeutic target for preventing and treating IA. 00, 000-000.
颅内动脉瘤（IA）是一种严重的脑血管疾病，与血管平滑肌细胞（VSMC）的表型转换和凋亡密切相关。本研究旨在探讨circGNAQ在IA发生发展中的作用，并阐明其潜在的分子机制。逆转录定量聚合酶链反应和荧光原位杂交显示，circGNAQ在IA组织中显著上调，主要定位于VSMC内。在体外，敲低circGNAQ可减弱过氧化氢诱导的VSMC表型转换和凋亡，而过表达circGNAQ则加剧这些病理过程。RNA下拉和质谱分析表明，circGNAQ特异性结合富含丝氨酸/精氨酸的剪接因子1（SRSF1），促进其泛素化和降解，从而使SRSF1不稳定。共转染实验证实，SRSF1在调节VSMC表型转换和凋亡中作为circGNAQ的下游介质发挥作用。在体内，敲低circGNAQ可通过抑制VSMC表型转换和凋亡显著抑制小鼠模型中IA的形成。本研究确定circGNAQ是通过靶向SRSF1调节VSMC表型转换和凋亡的新型调节因子。这些发现突出了circGNAQ作为预防和治疗IA的潜在治疗靶点。 00, 000 - 000。
