Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, Xi'an, China.
Department of Endocrinology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Eur J Pharm Biopharm. 2024 Apr;197:114218. doi: 10.1016/j.ejpb.2024.114218. Epub 2024 Feb 15.
Myocardial ischemia/reperfusion (MI/R) injury is the primary cause of postischemicheartfailure. The increased expression of Thioredoxin-interacting protein (TXNIP) has been implicated in MI/R injury, although the detailed mechanism remains incompletely understood. In the present study, we observed the up-regulation of the m6A mRNA methylation complex component Wilms' tumor 1-associating protein (WTAP) in MI/R mice, which led to the m6A modification of TXNIP mRNA and an increase in mRNA abundance. Knock-down of WTAP resulted in a significant reduction in the m6A level of TXNIP mRNA and down-regulated TXNIP expression. Moreover, exosomes engineered with ischemic myocardium-targeting peptide (IMTP) were able to deliver WTAP siRNA into ischemic myocardial tissues, resulting in a specific gene knockdown and myocardial protection. In summary, our findings demonstrate that the WTAP-TXNIP regulatory axis plays a significant role in postischemicheartfailure, and the use of engineered exosomes targeting the ischemic heart shows promise as a strategy for siRNA therapy to protect the heart from injury.
心肌缺血/再灌注（MI/R）损伤是缺血性心力衰竭的主要原因。虽然其详细机制尚不完全清楚，但已有研究表明，硫氧还蛋白相互作用蛋白（TXNIP）的表达增加与 MI/R 损伤有关。在本研究中，我们观察到 MI/R 小鼠中 m6A mRNA 甲基化复合物成分 Wilms 瘤 1 相关蛋白（WTAP）的上调，导致 TXNIP mRNA 的 m6A 修饰和 mRNA 丰度增加。WTAP 的敲低导致 TXNIP mRNA 的 m6A 水平显著降低，并下调 TXNIP 表达。此外，带有缺血性心肌靶向肽（IMTP）的工程化外泌体能够将 WTAP siRNA 递送至缺血性心肌组织，从而实现特异性基因敲低和心肌保护。总之，我们的研究结果表明，WTAP-TXNIP 调控轴在缺血性心力衰竭中起着重要作用，而针对缺血性心脏的工程化外泌体的应用有望成为一种用于 siRNA 治疗以保护心脏免受损伤的策略。
