FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

作者：Xin Zhang, Can Hu, Chun‐Yan Kong, Peng Song, Hai‐Ming Wu, Si‐Chi Xu, Yu‐Pei Yuan, Wei Deng, Zhen‐Guo Ma, Qizhu Tang · 发表于：Cell Death and Differentiation · 年份：2019 · DOI：10.1038/s41418-019-0372-z · 被引用次数：452 · 研究领域：Mitochondrial Function and Pathology、Chemotherapy-induced cardiotoxicity and mitigation、Electron Spin Resonance Studies

Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstra...