血管平滑肌细胞中SRRM4对REST基因的RNA剪接促进腹主动脉瘤发展

Background: The progression of abdominal aortic aneurysm (AAA) is closely associated with the phenotypic switch of vascular smooth muscle cells (VSMC). While members of the Serine/Arginine-rich splicing factor (SRs) superfamily are increasingly acknowledged for their pivotal role in modulating cell phenotype, the specific contribution of these factors to AAA development has remained underexplored. Methods: Through integrated analyses the whole transcriptome of human and murine AAA tissues derived from clinical samples and animal models, we identified serine-arginine repeat matrix 4 (SRRM4) as a candidate gene regulating AAA formation. To investigate the role of SRRM4 in AAA formation, we used global and VSMC-specific SRRM4-knockout mice to construct AAA mouse models in two different ways. The impact of SRRM4 on AAA was further investigated in in vivo and in vitro models Results: Elevated levels of SRRM4 mRNA and protein were observed in VSMC from both human and murine AAA tissues. Targeted silencing of SRRM4 in VSMC (but not in endothelial or myeloid cells) significantly attenuated AAA formation in both AngII-and CaCl2-induced mouse models. Our results identify the RE1 silencing transcription factor (REST) as a critical target gene of SRRM4 in AAA, a master regulator of cellular phenotypic stability. We show that SRRM4 modulates VSMC phenotype through alternative splicing of the REST gene, resulting in a non-functional REST4 isoform. Furthermore, our study shows that REST directly represses STAT1, a mechanism by which SRRM4 influences VSMC phenotypic transition. Regarding clinical significance, inhibition of both STAT1 expression and function was shown to be beneficial in preventing AAA formation and slowing disease progression in mouse models. Conclusions: This investigation uncovers a previously unrecognized role of SRRM4-mediated splicing of the REST gene in the progression of AAA and identifies a novel REST/STAT1 axis critical in the phenotypic modulation of VSMC. The findings of this study may provide insights for the development of innovative therapeutic strategies for AAA.