Fibroblast growth factor 21 protects the heart from apoptosis in a diabetic mouse model via extracellular signal-regulated kinase 1/2-dependent signalling pathway

Abstract

Aims/hypothesis This study investigated fibroblast growth factor 21 (FGF21)-mediated cardiac protection against apoptosis caused by diabetic lipotoxicity and explored the protective mechanisms involved. Methods Cardiac Fgf21 mRNA expression was examined in a diabetic mouse model using real-time PCR. After preincubation of palmitate-treated cardiac H9c2 cells and primary cardiomyocytes with FGF21 for 15 h, apoptosis and Fgf21-induced cell-survival signalling were investigated using small interfering (si)RNA and/or pharmacological inhibitors. We also examined the cardiac apoptotic signalling and structural and functional indices in wild-type and Fgf21-knockout (Fgf21-KO) diabetic mice.Results In a mouse model of type 1 diabetes, cardiac Fgf21 expression was upregulated about 40-fold at 2 months and 3-1.5-fold at 4 and 6 months after diabetes. FGF21 significantly reduced palmitate-induced cardiac apoptosis. Mechanistically, palmitate downregulated, but FGF21 upregulated, phosphorylation levels of extracellular signal-regulated kinase (ERK)1/ 2, mitogen-activated protein kinase 14 (p38 MAPK) and AMP-activated protein kinase (AMPK). Inhibition of each kinase with its inhibitor and/or siRNA revealed that FGF21 prevents palmitate-induced cardiac apoptosis via upregulating the ERK1/2-dependent p38 MAPK-AMPK signalling pathway. In vivo administration of FGF21, but not FGF21 plus ERK1/2 inhibitor, to diabetic or fatty-acid-infused mice significantly prevented cardiac apoptosis and reduced inactivation of ERK1/2, p38 MAPK and AMPK and prevented cardiac remodelling and dysfunction. The Fgf21-KO mice were more susceptible to diabetes-induced cardiac apoptosis, and this could be prevented by administration of FGF21. Deletion of Fgf21 did not further exacerbate cardiac dysfunction. Conclusions/interpretation These results demonstrate that FGF21 prevents lipid-or diabetes-induced cardiac apoptosis by activating the ERK1/2-p38 MAPK-AMPK pathway. FGF21 may be a therapeutic target for the treatment of diabetes-related cardiac damage.Electronic supplementary material The online version of this article

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

“…However, this elevation of AMPK activation was strongly attenuated in FGF21 KO mice, suggesting that FGF21 may be involved in the regulation of AMPK activity in response to restoring cardiac-energy homeostasis in STZ/HFD-induced diabetic mice. On the other hand, FGF21 inhibits palmitate-induced down-regulation of AMPK activation in cultured cardiomyocytes [19]. Consistent with these reports, our in vitro results also demonstrated that treatment with FGF21 significantly improved the activation of AMPK in response to HG-induced cytotoxicity in primary cardiomyocytes, and genetic inhibition of AMPK signaling markedly abrogated the protective effect of FGF21, suggesting that AMPK plays an indispensable role in FGF21 protection against HG-induced cardiomyocyte injury.…”

“…AMPK is significantly activated in response to cardiac energy imbalance during myocardial ischemia and myocardial infarction, and inactivation of AMPK was found to enhance myocardial injury during ischemia-reperfusion in mice [32,49]. Recently, we indicated that FGF21 protects against cardiac apoptosis in a type 1 diabetic mouse model by activating the extracellular signal-regulated kinase (ERK) 1/2-p38 mitogen-activated protein kinase (MAPK)-AMPK pathway [19], and pharmaceutical inhibition of AMPK led to a significant decrease in FGF21-induced cardioprotection and restoration of cardiac function in response to global ischemia [12]. In the present study, our in vivo data indicate that cardiac activation of AMPK was markedly upregulated in STZ/HFD-induced diabetic mice.…”

Effects of fibroblast growth factor 21 on the heart

“…Moreover, FGF21 can protect the heart from apoptosis by activation of the Erk1/2-p38 MAPK-AMPK survival pathway (Zhang et al 2015a). Evidence from these reports confirmed that FGF21 plays a critical role in myocardial protection and anti-apoptosis following myocardial injury (Patel et al 2014, Joki et al 2015, Zhang et al 2015a). Due to the potential cardioprotective benefits of FGF21, it is possible that FGF21 could be used to prevent and/or treat the myocardial apoptosis due to I/R injury or MI.…”

“…Moreover, FGF21 deficiency accelerated the development of diabetic cardiomyopathy (DCM) (Yan et al 2015). In contrast, FGF21 administration also prevents lipotoxicity and diabetes induced cardiac apoptosis in DCM (Zhang et al 2015a).…”

“…Fourth, increased myocardial collagen accumulation was observed as shown by increased connective tissue growth factor (CTGF). In contrast, FGF21 administration can protect the heart from lipotoxicity and diabetes induced cardiac apoptosis by the activating of the Erk1/2-p38 MAPK-AMPK survival pathway leading to decreased cardiac apoptosis and improved cardiac function (Zhang et al 2015a). An illustrated diagram of these mechanisms is shown in Fig.…”