血管平滑肌
新生内膜
细胞生物学
下调和上调
基因沉默
生物
表型
表型转换
信号转导
发病机制
小发夹RNA
壁细胞
RNA干扰
信使核糖核酸
细胞生长
转录因子
基因剔除小鼠
基因敲除
STAT蛋白
激活剂(遗传学)
小干扰RNA
细胞
癌症研究
车站3
基因表达
心肌细胞
斑马鱼
基因表达调控
血管疾病
胚胎血管重塑
作者
Huawei Zhang,Jing Liu,Daqian Sun,Yuxiu Liu,Wenhao Sun,Shanshan Wang,Xiuqin Xu,Huawei Zhang,Jing Liu,Daqian Sun,Yuxiu Liu,Wenhao Sun,Shanshan Wang,Xiuqin Xu
摘要
Abstract Aims Vascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets. Methods and results We established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation, and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling. Conclusion This study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.
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