Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Diseases, the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081, China.
Front Med. 2024 Jun;18(3):499-515. doi: 10.1007/s11684-023-1052-4. Epub 2024 May 28.
Cardiac fibrosis caused by ventricular remodeling and dysfunction such as post-myocardial infarction (MI) can lead to heart failure. RNA N-methyladenosine (mA) methylation has been shown to play a pivotal role in the occurrence and development of many illnesses. In investigating the biological function of the mA reader YTHDF1 in cardiac fibrosis, adeno-associated virus 9 was used to knock down or overexpress the YTHDF1 gene in mouse hearts, and MI surgery in vivo and transforming growth factor-β (TGF-β)-activated cardiac fibroblasts in vitro were performed to establish fibrosis models. Our results demonstrated that silencing YTHDF1 in mouse hearts can significantly restore impaired cardiac function and attenuate myocardial fibrosis, whereas YTHDF1 overexpression could further enhance cardiac dysfunction and aggravate the occurrence of ventricular pathological remodeling and fibrotic development. Mechanistically, zinc finger BED-type containing 6 mediated the transcriptional function of the YTHDF1 gene promoter. YTHDF1 augmented AXL translation and activated the TGF-β-Smad2/3 signaling pathway, thereby aggravating the occurrence and development of cardiac dysfunction and myocardial fibrosis. Consistently, our data indicated that YTHDF1 was involved in activation, proliferation, and migration to participate in cardiac fibrosis in vitro. Our results revealed that YTHDF1 could serve as a potential therapeutic target for myocardial fibrosis.
心脏纤维化是由心室重构和功能障碍引起的，如心肌梗死后（MI），可导致心力衰竭。RNA N6-甲基腺苷（mA）甲基化已被证明在许多疾病的发生和发展中起关键作用。在研究 mA 读蛋白 YTHDF1 在心脏纤维化中的生物学功能时，我们使用腺相关病毒 9 在小鼠心脏中敲低或过表达 YTHDF1 基因，并在体内进行 MI 手术和体外转化生长因子-β（TGF-β）激活的心肌成纤维细胞，以建立纤维化模型。我们的结果表明，在小鼠心脏中沉默 YTHDF1 可以显著恢复受损的心脏功能并减轻心肌纤维化，而过表达 YTHDF1 则可以进一步加重心脏功能障碍并加重心室病理性重塑和纤维化的发生。在机制上，锌指 BED 型包含 6 介导 YTHDF1 基因启动子的转录功能。YTHDF1 增强了 AXL 的翻译并激活了 TGF-β-Smad2/3 信号通路，从而加重了心脏功能障碍和心肌纤维化的发生和发展。一致地，我们的数据表明 YTHDF1 参与了心肌成纤维细胞的激活、增殖和迁移，以参与心脏纤维化。我们的研究结果表明，YTHDF1 可能成为心肌纤维化的潜在治疗靶点。
