Wu Jiawei, Li Zihan, Wang Yuwei, Hu Hao, Ma Likun
Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, China.
Department of Cardiology, The First Affiliated Hospital of USTC, Division of Life Science and Medicine, University of Science and Technology of China, Hefei 230001, China.
Int Immunopharmacol. 2025 Sep 11;165:115473. doi: 10.1016/j.intimp.2025.115473.
Myocardial ischemia/reperfusion (I/R) injury primarily results from mitochondrial dysfunction and cardiomyocyte death. Mitophagy helps maintain mitochondrial function and offers protective effects to reperfused cardiac tissue. Interleukin-6 (IL-6), a cytokine released in response to acute injury, is expressed by multiple cell types, including cardiomyocytes. Recombinant IL-6 has been shown to limit myocardial infarctions in mice, suggesting its cardioprotective potential. This study aimed to explore the role of mitophagy in IL-6-induced cardioprotection and the underlying cellular mechanisms. Our findings revealed that silencing IL-6 with cardiotropic recombinant adeno-associated virus serotype 9 (rAAV9) in mouse hearts led to a significant increase in infarct sizes during myocardial I/R. We assessed mitophagy by analyzing mitophagy flux and related proteins. The results indicated that IL-6 knockdown notably reduced mitophagy induced by myocardial I/R both in vivo and in vitro. Additionally, myocardial I/R caused a significant rise in Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3), which was reversed by IL-6 silencing. Importantly, BNIP3 deficiency countered the mitophagy induced by recombinant IL-6 and nullified its cardioprotective effects. Mechanistically, IL-6 was shown to enhance the translocation of forkhead transcription factor Foxo3a to the nucleus, which increased the transcriptional activity of Foxo3a, leading to elevated BNIP3 levels in cardiomyocytes. BNIP3 was identified as a transcriptional target of Foxo3a, with Foxo3a binding to the BNIP3 promoter to activate its transcription. Notably, deletion of Foxo3a reduced the cardioprotective effects of recombinant IL-6. Based on these results, we propose that direct stimulation of mitophagy represents a novel mechanism through which IL-6 protects cardiomyocytes from myocardial I/R injury.
心肌缺血/再灌注（I/R）损伤主要源于线粒体功能障碍和心肌细胞死亡。线粒体自噬有助于维持线粒体功能，并为再灌注的心脏组织提供保护作用。白细胞介素-6（IL-6）是一种在急性损伤时释放的细胞因子，由多种细胞类型表达，包括心肌细胞。重组IL-6已被证明可限制小鼠心肌梗死，表明其具有心脏保护潜力。本研究旨在探讨线粒体自噬在IL-6诱导的心脏保护中的作用及潜在的细胞机制。我们的研究结果显示，用嗜心肌重组腺相关病毒9型（rAAV9）沉默小鼠心脏中的IL-6会导致心肌I/R期间梗死面积显著增加。我们通过分析线粒体自噬通量和相关蛋白来评估线粒体自噬。结果表明，IL-6基因敲低显著降低了体内和体外心肌I/R诱导的线粒体自噬。此外，心肌I/R导致Bcl-2/腺病毒E1B 19 kDa相互作用蛋白3（BNIP3）显著升高，而IL-6沉默可使其逆转。重要的是，BNIP3缺陷可对抗重组IL-6诱导的线粒体自噬并消除其心脏保护作用。机制上，IL-6可增强叉头转录因子Foxo3a向细胞核的转位，从而增加Foxo3a的转录活性，导致心肌细胞中BNIP3水平升高。BNIP3被确定为Foxo3a的转录靶点，Foxo3a与BNIP3启动子结合以激活其转录。值得注意的是，删除Foxo3a可降低重组IL-6的心脏保护作用。基于这些结果，我们提出直接刺激线粒体自噬是IL-6保护心肌细胞免受心肌I/R损伤的一种新机制。
