心脏纤维化
纤维化
生物
成纤维细胞
心肌纤维化
自噬
细胞生物学
下调和上调
病理
医学
细胞培养
遗传学
基因
细胞凋亡
作者
Ji-Fei Ding,Bin Tu,Kai Song,Lei Zhu,Li-Chan Lin,Lei Zhu,Yan Shi,Jingjing Yang,Jian‐Yuan Zhao,Hui Tao
出处
期刊:Cardiovascular Research
[Oxford University Press]
日期:2024-11-05
摘要
Abstract Background Mechanosensitive ion channels play a key role in heart development, physiology, and disease. However, little is known about the molecular mechanisms of the mechanosensitive nonselective cationic channel Piezo family in cardiac fibrosis. Methods and Results Mice were treated with ISO/Ang-II/TAC to induce cardiac fibrosis. AAV9 carrying POSTN promoter-driven small hairpin RNA targeting YTHDF1, and Piezo2 were administered to ISO mice to investigate their roles in cardiac fibrosis. RNA-seq, single-cell sequencing, and histological and biochemical analyses were performed to determine the mechanism by which YTHDF1 regulates Piezo2 expression in cardiac fibrosis. Piezo2 was reconstituted in YTHDF1-deficient cardiac fibroblasts and mouse hearts to study its effects on cardiac fibroblast autophagy and fibrosis. Piezo2 but not Piezo1 expression increased in experimental cardiac fibrosis and TGF-β1-induced cardiac fibroblasts. Fibroblast-specific Piezo2 deficiency ameliorated fibroblast activation and autophagy and inhibited cardiac fibrosis. Mechanistically, Piezo2 upregulation was associated with elevated m6A mRNA levels. Site-specific m6A modifications at peak_26355 were crucial for regulating the binding of YTHDF1 to Piezo2 mRNA and inducing Piezo2 translation. Notably, Piezo2 epitranscriptomic repression ameliorated experimental cardiac fibrosis. Conclusions We demonstrated a novel epitranscriptomic mechanism through which YTHDF1 recognizes Piezo2 and controls cardiac fibroblast autophagy and fibrosis through m6A-dependent modulation. Our findings provide new insights for the development of preventive measures for cardiac fibrosis.
科研通智能强力驱动
Strongly Powered by AbleSci AI