Deficiency of the RNA-binding protein RBMS1 improves myocardial fibrosis and heart failure

作者：Liangliang Li, Jiayu Guo, Jiayue Feng, Tianyu Li, Bingqian Xu, Wei Li, Na Yang, Weihang Ji, Shuping Zhuang, Yiding Geng, Bin Wang, Jinping Liu, Jian Sun, Yingying Guo, Ruoxuan Yang, Zhiwei Ning, Yan Wang, Qiudi Liu, Xiong Tian, Hongli Shan, Baofeng Yang, Haihai Liang · 发表于：European Heart Journal · 年份：2025 · DOI：10.1093/eurheartj/ehaf370 · 被引用次数：14 · 研究领域：Cardiomyopathy and Myosin Studies、Congenital heart defects research、RNA Research and Splicing

BACKGROUND AND AIMS: Previous studies have highlighted the significance of RNA-binding proteins and alternative splicing (AS) in the progression of complex diseases, but the specific involvement of AS in heart failure (HF) remains unclear. This study aimed to elucidate the role of RNA-binding motif single-stranded interacting protein 1 (RBMS1), an RNA-binding protein, in the development of HF by regulating AS and its effect on cardiac fibrosis. METHODS: The level of RBMS1 was investigated in the hearts of both HF patients and mice. Fibroblast-specific knockout RBMS1 mice were generated to investigate the role of RBMS1 in cardiac fibrosis and HF. Unbiased RNA sequencing and RNA immunoprecipitation combined with RNA pull-down were conducted to identify the downstream effector of RBMS1 in fibroblasts. RESULTS: RBMS1 expression was increased in murine hearts following myocardial infarction, as well as in the hearts of patients with ischaemic cardiomyopathy and hypertrophic cardiomyopathy. Moreover, RBMS1 levels in the hearts of HF patients were positively associated with cardiac fibrosis. Furthermore, fibroblast-specific ablation of RBMS1 improved cardiac dysfunction by mitigating myocardial fibrosis. Mechanistically, RBMS1 regulated the alternative splicing of LIM domain 7 (LMO7) by binding to intron 19 and splicing out exon 20, resulting in the formation of the LMO7-Δe20 isoform, which thus activated the transforming growth factor (TGF)-β1 pathway by upregulating activator prot...