Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China; Department of Cardiothoracic Surgery, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, Jiangsu Province, PR China.
Department of Cardiothoracic Surgery, The Second Hospital of Anhui Medical University, Hefei, 230601, PR China.
Eur J Pharmacol. 2023 Mar 5;942:175494. doi: 10.1016/j.ejphar.2023.175494. Epub 2023 Jan 16.
Cardiac fibrosis remains an unresolved problem in heart disease. Its etiology is directly caused by the activation and proliferation of cardiac fibroblasts (CFs). However, there is limited information regarding the biological role of cardiac fibroblasts in cardiac fibrosis. Herein, we screened out a gene, IGFBP3, whose expression significantly increased in TGF-β1-stimulated human primary CFs by mining RNA-Seq data for differential and WGCNA. We verified the IGFBP3's expression in transverse aortic constriction (TAC) surgery, isoproterenol (ISO)-induced cardiac fibrosis models, and TGFβ1-stimulated mouse primary CFs. We also found that the knockdown of IGFBP3 could inhibit the migration and proliferation ability of CFs. Furthermore, we found that aberrant N6-methyladenosine(mA) mRNA modifications in the animal model and activated CFs may regulate the expression of IGFBP3 in developing cardiac fibrosis. Silencing METTL3 could downregulate the expression of IGFBP3 and inhibit the activation of CFs and the degree of cardiac fibrosis both in vitro and in vivo. Indeed, we also verified the expression of METTL3 and IGFBP3 in the atrial tissues of patients with atrial fibrillation (AF). Thus, METTL3 may regulate IGFBP3's expression and CFs activation via RNA epigenetic modifications, laying the foundation for a specific and novel therapeutic target in cardiac fibrosis.
心肌纤维化仍然是心脏病领域尚未解决的问题。其病因直接由心脏成纤维细胞（CFs）的激活和增殖引起。然而，关于心脏成纤维细胞在心肌纤维化中的生物学作用的信息有限。在此，我们通过挖掘 RNA-Seq 数据中的差异和 WGCNA，筛选出一个基因 IGFBP3，其在 TGF-β1 刺激的人原代 CFs 中的表达显著增加。我们验证了 IGFBP3 在主动脉缩窄（TAC）手术、异丙肾上腺素（ISO）诱导的心肌纤维化模型和 TGFβ1 刺激的小鼠原代 CFs 中的表达。我们还发现 IGFBP3 的敲低可以抑制 CFs 的迁移和增殖能力。此外，我们发现动物模型和激活的 CFs 中异常的 N6-甲基腺苷（m6A）mRNA 修饰可能调节 IGFBP3 在心肌纤维化发展过程中的表达。沉默 METTL3 可以下调 IGFBP3 的表达，并抑制 CFs 的激活和心肌纤维化的程度，无论是在体外还是体内。事实上，我们还验证了心房颤动（AF）患者心房组织中 METTL3 和 IGFBP3 的表达。因此，METTL3 可能通过 RNA 表观遗传修饰调节 IGFBP3 的表达和 CFs 的激活，为心肌纤维化的特定和新颖的治疗靶点奠定基础。
