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

Autor: Zhang X; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Hu C; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Kong CY; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Song P; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Wu HM; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Xu SC; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Yuan YP; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Deng W; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China., Ma ZG; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China. zhengma@whu.edu.cn.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China. zhengma@whu.edu.cn.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China. zhengma@whu.edu.cn., Tang QZ; Department of Cardiology, Renmin Hospital of Wuhan University, 430060, Wuhan, PR China. qztang@whu.edu.cn.; Cardiovascular Research Institute of Wuhan University, 430060, Wuhan, PR China. qztang@whu.edu.cn.; Hubei Key Laboratory of Cardiology, 430060, Wuhan, PR China. qztang@whu.edu.cn.
Jazyk: angličtina
Zdroj: Cell death and differentiation [Cell Death Differ] 2020 Feb; Vol. 27 (2), pp. 540-555. Date of Electronic Publication: 2019 Jun 17.
DOI: 10.1038/s41418-019-0372-z
Abstrakt: 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 demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.
Databáze: MEDLINE
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