Cardioprotective effects of fibroblast growth factor 21 against doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway

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.

Therapeutic effects of higenamine combined with [6]‐gingerol on chronic heart failure induced by doxorubicin via ameliorating mitochondrial function

“…It is noteworthy that the LKB1/AMPK/Sirt1 axis and its downstream targets are highly sensitive targets for DOX‐induced cardiac injury . SIRT1 is reported to have a critical role in controlling the cardiac LKB1/AMPK pathway . Activated Sirt1 can also regulate the activity of the peroxisome proliferator‐activated receptor gamma coactivator 1 alpha (PGC‐1α) and further up‐regulate its expression .…”

PGC‐1α, a potential therapeutic target against kidney aging

“…FGF21, a hormone‐like member of the FGF family, is induced by endoplasmic reticulum (ER) stress, mitochondrial dysfunction, and autophagy (Suwa et al, ). FGF21 controls energy metabolism by enhancing energy expenditure, ameliorates age‐related metabolic disorders such as atherosclerosis, obesity, and T2DM (Suwa et al, ), upregulates hepatic PGC‐1α expression (Potthoff et al, ), increases NAD levels leading to the activation of SIRT1 and the deacetylation of PGC‐1α that consequently activates PGC‐1α in adipocytes (Chau, Gao, Yang, Wu, & Gromada, ), and enhances SIRT1 binding to liver kinase B (LKB1), which decreases LKB1 acetylation and subsequently induces the activation of AMPK in cardiomyocytes (Wang, Wang, Zhang, Liu, & Gu, ). The transgenic overexpression of FGF21 extends the lifespan of mice by blunting the growth hormone/insulin‐like growth factor 1 signaling pathway in the liver (Zhang et al, ).…”

β‐LAPachone ameliorates doxorubicin‐induced cardiotoxicity via regulating autophagy and Nrf2 signalling pathways in mice

“…In favour of these findings, it has been demonstrated that dunnione, a natural quinone with extensive structural analogies to B-LAP, elevates nuclear presence of Nrf2 and simultaneously up-regulates the expressions of HO-1 and NQO1 in the kidneys of cisplatin nephrotoxic rats. 28 Additionally, Wang et al 29 showed that the activation of SIRT/LKB1/AMPK signalling pathway protects H9c2 cells, adult mice cardiomyocytes and 129S1/ SyImJ mice against DOX-induced cardiotoxicity through anti-oxidative, anti-apoptotic and anti-inflammatory actions. Moreover, it was reported that DOX-induced cardiotoxicity can be reversed by activation of Sirt1/AMPK/Nrf2 pathway by suppression of intracellular oxidative stress.…”