Myocardial mitochondrial antiviral signaling protein promotes heart Ischemia-reperfusion injury via RIG-I signaling in mice
Zhenyu Kang, Mengling Yang, Yue Liu, Gui Yang, Yalan Dong, Haifeng Zhou, Zili Zhang, Mingyue Li, Heng Fan, Zheng Li, Junjie Lu, Junyi Li, Rui Zhu, Chengyu Yin, Boyi Liu, Feng Jiang, Kun Huang, Alexey Sarapultsev, Fangfei Li, Ge Zhang, Ling Zhao, Yan‐Yi Wang, Yun‐Jia Ning, Xiang Cheng, Sarajo K. Mohanta, Changjun Yin, Shanshan Luo, Andreas J. R. Habenicht, Desheng Hu
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. The role of outer mitochondrial membrane proteins in Myocardial Ischemia-reperfusion Injury (MIRI) largely remains unknown. Here, the authors demonstrate that the outer mitochondrial membrane protein Myocardial Mitochondrial Antiviral Signaling (MAVS) protein promotes MIRI suggesting MAVS protein as potential therapeutic target.