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2017 ; 8
(8
): e3018
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Cardioprotective effects of fibroblast growth factor 21 against
doxorubicin-induced toxicity via the SIRT1/LKB1/AMPK pathway
#MMPMID28837153
Wang S
; Wang Y
; Zhang Z
; Liu Q
; Gu J
Cell Death Dis
2017[Aug]; 8
(8
): e3018
PMID28837153
show ga
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-? and interleukin-6) via the IKK/I?B?/nuclear factor-?B 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.
|AMP-Activated Protein Kinase Kinases
[MESH]
|AMP-Activated Protein Kinases/*metabolism
[MESH]
|Animals
[MESH]
|Cardiotoxicity/*etiology
[MESH]
|Doxorubicin/*toxicity
[MESH]
|Fibroblast Growth Factors/pharmacology/*therapeutic use
[MESH]
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