SAMD4A inhibits abdominal aortic aneurysm development and VSMC phenotypic transformation through targeting KDM2B.

INTRODUCTION: Abdominal aortic aneurysm (AAA) is a fatal vascular disease without effective drug treatments. Pathological vascular smooth muscle cell (VSMC) phenotypic transformation is the underlying cause of AAA. However, the underlying mechanism has not been fully elucidated. OBJECTIVE: We aimed to determine whether the RNA binding protein SAMD4A suppresses VSMC phenotype transformation and inhibits AAA formation. METHODS: Single-cell RNA sequencing (scRNA-seq) was conducted to reveal smooth muscle cell phenotypic heterogeneity and RNA-binding protein dysregulation during AAA formation. A pancreatic elastase (PPE)-induced mouse AAA model was generated to confirm the function of SAMD4A in vivo. RNA-seq combined with RNA immunoprecipitation (RIP) sequencing and chromatin immunoprecipitation (ChIP)-qPCR was used for mechanistic exploration. RESULTS: We identified 3 smooth muscle cell subtypes, and demonstrated their transformation from contractile to inflammatory-like VSMCs during AAA formation. SAMD4A expression was increased in contractile VSMCs and significantly reduced in AAAs. The results of functional experiments revealed that VSMC-specific knockout of SAMD4A exacerbated PPE-induced AAA formation, whereas VSMC knock-in attenuated AAA formation. SAMD4A regulated VSMC contraction by binding to KDM2B. Further in vivo studies revealed that overexpression of KDM2B abolished the protective effect of SAMD4A in AAA. ChIP-qPCR demonstrated that KDM2B suppressed the transcription of VSMC contractile markers by binding to their promoters and reducing H3K4me3 and H3K36me2 levels. CONCLUSIONS: SAMD4A inhibits AAA development and VSMC phenotypic transformation by targeting KDM2B. This work highlights the potential of SAMD4A as a new therapeutic option to prevent AAA formation.