M2 macrophage-derived exosomes carry microRNA-148a to alleviate myocardial ischemia/reperfusion injury via inhibiting TXNIP and the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. (May 2020)

• Record Type: Journal Article
• Authors: Dai, Yuxiang; Wang, Shen; Chang, Shufu; Ren, Daoyuan; Shali, Shalaimaiti; Li, Chenguang; Yang, Hongbo; Huang, Zheyong; Ge, Junbo
• Is Part Of: Journal of molecular and cellular cardiology. Volume 142(2020)
• Page Start: 65
• Page End: 79
• Publication Date: 2020-05
• Subjects: M2 macrophages -- Exosomes -- MicroRNA-148a -- Myocardial ischemia/reperfusion injury -- Thioredoxin-interacting protein -- TLR4/NF-κB/NLRP3 inflammasome signaling pathway; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.02.007
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Background: Reperfusion may cause injuries to the myocardium in ischemia situation. Emerging studies suggest that exosomes may serve as key mediators in myocardial ischemia/reperfusion (MI/R) injury. Objective: The study was conducted to figure out the mechanism of M2 macrophage-derived exosomes (M2-exos) in MI/R injury with the involvement of microRNA-148a (miR-148a). Methods and results: M2 macrophages were prepared and M2-exos were collected and identified. Neonatal rat cardiomyocytes (NCMs) were extracted for in vitro hypoxia/reoxygenation (H/R) model establishment, while rat cardiac tissues were separated for in vivo MI/R model establishment. Differentially expressed miRNAs in NCMs and H/R-treated NCMs after M2-exos treatment were evaluated using microarray analysis. The target relation between miR-148a and thioredoxin-interacting protein (TXNIP) was identified using dual luciferase reporter gene assay. Gain- and loss- of function studies of miR-148a and TXNIP were performed to figure out their roles in MI/R injury. Meanwhile, the activation of the TLR4/NF-κB/NLRP3 inflammasome signaling pathway and pyroptosis of NCMs were evaluated. M2 macrophages carried miR-148a into NCMs. Over-expression of miR-148a enhanced viability of H/R-treated NCMs, reduced infarct size in vivo, and alleviated dysregulation of cardiac enzymes and Ca 2+ overload in both models. miR-148a directly bound to the 3′-untranslated region (3'UTR) of TXNIP. Over-expressed TXNIP triggered the TLR4/NF-κB/NLRP3 signaling pathway activation and induced cell pyroptosis of NCMs, and the results were reproduced in in vivo studies. Conclusion: This study demonstrated that M2-exos could carry miR-148a to mitigate MI/R injury via down-regulating TXNIP and inactivating the TLR4/NF-κB/NLRP3 inflammasome signaling pathway. This study may offer new insights into MI/R injury treatment. Highlights: M2 type macrophage-derived exosomes reduce mi/R injury. M2-exos carry miR-148a into MI/R tissues and cells. miR-148a alleviates dysregulation of cardiac enzymes and Ca 2+ overload. miR-148a negatively targets TXNIP expression miR-148a alleviates MI/R injury via inhibition of TXNIP/TLR4/NF-κB/NLRP3.