Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening complication of myocardial infarcts, with inner mitochondrial membrane protein dysfunction involved in MIRI-induced heart injury. The role of outer mitochondrial membrane protein mitochondrial antiviral signaling protein (MAVS) is unknown. Here, we show that MAVS expression increases in infarcted myocardium of male wild-type mice. Global MAVS-knock-out or myocardial-specific MAVS knockdown protects male mice from acute and chronic MIRI. MIRI induces double-stranded RNA in affected myocardium, activating intracellular retinoic acid-inducible gene I (RIG-I) signaling, which leads to MAVS aggregation and subsequent non-canonical downstream signaling. MAVS aggregates recruit tumor necrosis factor-associated factor family 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), the activating mitogen-activated protein kinase (MAPK) pathway and apoptosis. MAVS-knock-out reduces c-jun-NH2 terminal kinase (JNK) phosphorylation and apoptosis. JNK inhibition protects against MIRI in wild-type male mice, whereas JNK agonist impairs protection in MAVS-knock-out male mice. MIRI activates RIG-I/MAVS pathway and subsequently triggers the TAK1/TRAF6 complex, leading to the activation of the MAPK/JNK signaling cascade. This sequential activation cascade may serve as a potential therapeutic target for MIRI.

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Publication Details

Journal
Nature Communications
Published
2025-06-02
DOI
https://doi.org/10.1038/s41467-025-60123-7
Citations
7
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
5.58

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article

Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice

Desheng Hu, Yun‐Jia Ning, Alexey Sarapultsev, Zhenyu Kang et al.
7 citations
Nature Communications
interferon and immune responses
5.58
article

Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice

Desheng Hu, Yun‐Jia Ning, Alexey Sarapultsev, Zhenyu Kang, Yalan Dong, Sarajo K. Mohanta, Chengyu Yin, Xiang Cheng, Boyi Liu, Feng Jiang, Andreas J. R. Habenicht, Yan‐Yi Wang, Ling Zhao, Yue Liu, Ge Zhang, Junyi Li, Changjun Yin, Mingyue Li, Fangfei Li, Heng Fan, Mengling Yang, Kun Huang, Shanshan Luo, Gui Yang, Rui Zhu, Haifeng Zhou, Zili Zhang, Zheng Li, Jackson G. Lu
article en
7 citations

Abstract

Myocardial ischemia-reperfusion injury (MIRI) is a life-threatening complication of myocardial infarcts, with inner mitochondrial membrane protein dysfunction involved in MIRI-induced heart injury. The role of outer mitochondrial membrane protein mitochondrial antiviral signaling protein (MAVS) is unknown. Here, we show that MAVS expression increases in infarcted myocardium of male wild-type mice. Global MAVS-knock-out or myocardial-specific MAVS knockdown protects male mice from acute and chronic MIRI. MIRI induces double-stranded RNA in affected myocardium, activating intracellular retinoic acid-inducible gene I (RIG-I) signaling, which leads to MAVS aggregation and subsequent non-canonical downstream signaling. MAVS aggregates recruit tumor necrosis factor-associated factor family 6 (TRAF6) and transforming growth factor-β-activated kinase 1 (TAK1), the activating mitogen-activated protein kinase (MAPK) pathway and apoptosis. MAVS-knock-out reduces c-jun-NH2 terminal kinase (JNK) phosphorylation and apoptosis. JNK inhibition protects against MIRI in wild-type male mice, whereas JNK agonist impairs protection in MAVS-knock-out male mice. MIRI activates RIG-I/MAVS pathway and subsequently triggers the TAK1/TRAF6 complex, leading to the activation of the MAPK/JNK signaling cascade. This sequential activation cascade may serve as a potential therapeutic target for MIRI.

Nature CommunicationsVol. 16(1)
South Ural State University (RU), Tianjin University of Traditional Chinese Medicine (CN), Union Hospital (HK), Hong Kong Baptist University (HK), Sun Yat-sen University (CN), Biocon (Switzerland) (CH), Chinese Academy of Sciences (CN), Huazhong Agricultural University (CN), Zhongda Hospital Southeast University (CN), Wuhan Institute of Virology (CN), Nanjing Drum Tower Hospital (CN), Hubei University of Arts and Science (CN), Xiangyang Central Hospital (CN), HaCon (Germany) (DE), German Centre for Cardiovascular Research (DE), Xiyuan Hospital (CN), The First Affiliated Hospital, Sun Yat-sen University (CN), Wuhan Union Hospital (CN), The Third Affiliated Hospital of Zhejiang Chinese Medical University (CN), Union Hospital (CN), Huazhong University of Science and Technology (CN), Ludwig-Maximilians-Universität München (DE)
Corona-Stiftung, Deutsche Forschungsgemeinschaft, National Natural Science Foundation of China, National Science and Technology Major Project, European Research Area Network on Cardiovascular Diseases
Good health and well-being
Openalex Percentile: Top 4%
interferon and immune responses
5.58
DOIOpen Access PDFOpenAlex
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