RBM24 regulates phenotypic switching of smooth muscle cell in vascular remodeling by stabilizing JAK2 mRNA

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.