Abstract
Doxorubicin (DOX) is a highly effective antineoplastic anthracycline drug; however, the adverse effect of the cardiotoxicity has limited its widespread application. Fibroblast growth factor 21 (FGF21), as a well-known regulator of glucose and lipid metabolism, was recently shown to exert cardioprotective effects. The aim of this study was to investigate the possible protective effects of FGF21 against DOX-induced cardiomyopathy. We preliminarily established DOX-induced cardiotoxicity models in H9c2 cells, adult mouse cardiomyocytes, and 129S1/SyImJ mice, which clearly showed cardiac dysfunction and myocardial collagen accumulation accompanying by inflammatory, oxidative stress, and apoptotic damage. Treatment with FGF21 obviously attenuated the DOX-induced cardiac dysfunction and pathological changes. Its effective anti-inflammatory activity was revealed by downregulation of inflammatory factors (tumor necrosis factor-α and interleukin-6) via the IKK/IκBα/nuclear factor-κB pathway. The anti-oxidative stress activity of FGF21 was achieved via reduced generation of reactive oxygen species through regulation of nuclear transcription factor erythroid 2-related factor 2 transcription. Its anti-apoptotic activity was shown by reductions in the number of TUNEL-positive cells and DNA fragments along with a decreased ratio of Bax/Bcl-2 expression. In a further mechanistic study, FGF21 enhanced sirtuin 1 (SIRT1) binding to liver kinase B1 (LKB1) and then decreased LKB1 acetylation, subsequently inducing AMP-activated protein kinase (AMPK) activation, which improved the cardiac inflammation, oxidative stress, and apoptosis. These alterations were significantly prohibited by SIRT1 RNAi. The present work demonstrates for the first time that FGF21 obviously prevented DOX-induced cardiotoxicity via the suppression of oxidative stress, inflammation, and apoptosis through the SIRT1/LKB1/AMPK signaling pathway.
Highlights
1807 cancer survivors followed for 7 years showed that 33% died of heart diseases.[2]
This result was continuously confirmed by quantitative real-time PCR for collagen I mRNA expression (Figure 1b) and found that DOX-induced collagen I increase was obviously blocked by pre-administration of Fibroblast growth factor 21 (FGF21)
DOX-induced cardiac fibrosis was verified by increased expression of pro-fibrotic mediators, connective tissue growth factor (CTGF) and transforming growth factor β (TGF-β) (Figures 1c and d), and these elevations were almost completely prevented by FGF21 pre-treatment
Summary
1807 cancer survivors followed for 7 years showed that 33% died of heart diseases.[2]. Inflammation, and apoptosis have been proposed as the mechanisms of the DOX-induced cardiotoxicity, which at least could result in cardiac remodeling and dysfunction.[7] To date, no targeted strategies are available for preventing DOX-induced cardiotoxicity. The mechanisms of FGF21’s cardioprotective activity were analyzed using cardiomyoblasts (H9c2 cells), adult mouse cardiomyocytes, and a wild-type mouse model (129S1/ SvImJ) The results of these experiments demonstrated that the cytotoxicity of DOX to H9c2 cells, adult mouse cardiomyocytes, and the heart of 129S1/SvImJ mice can be attenuated by FGF21. Further mechanistic studies showed that FGF21 obviously prevented the DOX-induced cardiotoxicity via the suppression of oxidative stress, inflammation, and apoptosis through activating the SIRT1/liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) signaling pathway both in vitro and in vivo. Our findings indicate that FGF21 could be considered as a therapeutic target for the clinical treatment and prevention for DOX-induced cardiac injury
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