Possible role of fibroblast growth factor 21 on atherosclerosis via amelioration of endoplasmic reticulum stress-mediated apoptosis in apoE−/− mice

Abstract

Fibroblast growth factor 21 (FGF-21) is an endocrine factor that can be secreted into circulation by the liver. FGF-21 takes part in metabolic actions and is thought to be a promising candidate for the treatment of diabetes. However, the role of FGF-21 in atherosclerosis is unknown. In this study, apoE(-/-) mice were fed an atherogenic diet for 4 weeks with and without subcutaneous injections of FGF-21. ApoE(-/-) mice fed an atherogenic diet showed hyperlipidemia, a large plaque area in aortas and increased vessel wall thickness. Plasma FGF-21 content and protein level of FGF receptor 1 (FGFR1) in aortas was greater in apoE(-/-) than C57BL/6J mice. Exogenous FGF-21 treatment significantly ameliorated dyslipidemia in apoE(-/-) mice. FGF-21-treated apoE(-/-) mice showed reduced number of aortic plaques and plaque area as well as reduced number of TUNEL-positive cells. Protein levels of the endoplasmic reticulum stress markers glucose-regulated protein 94, caspase-12 and C/EBP homologous protein were reduced by 34.5, 31.4 and 26.5 %, respectively, in apoE(-/-) mice. Endogenous expression of FGF-21 and its receptor FGFR1 were upregulated in apoE(-/-) mice, and exogenous administration of FGF-21 ameliorated the atherogenic-induced dyslipidemia and vascular atherosclerotic lesions. FGF-21 protecting against atherosclerosis might be in part by its inhibitory effects on endoplasmic reticulum stress-mediated apoptosis.

Effects of fibroblast growth factor 21 on the heart

“…Moreover, in chronic MI (2 weeks) C57BL6 and adiponectin-KO mice models it was demonstrated that FGF21 protein derived from skeletal muscles protected the heart from apoptosis through adiponectin signaling (Joki et al 2015). In addition, FGF21 100 mg/kg per day s.c. injections for 4 weeks could protect the abdominal aorta from arteriosclerotic lesions through lipid regulation and ER stress induced vascular cell apoptosis in the ApoE-KO model (Wu et al 2014).…”

“…A previous study demonstrated that cardiomyocytes secrete FGF21 into the media culture in basal conditions at a rate of w0.05 ng/ml per 24 h (Planavila et al 2013). In the heart, FGF21 ligands act via the FGFR1c (Suzuki et al 2008, Liu et al 2013, Planavila et al 2013, Wu et al 2014, and FGFR3 (Suzuki et al 2008, Liu et al 2013, utilizing b-Klotho as a co-receptor (Suzuki et al 2008, Liu et al 2013, Planavila et al 2013. Endogenous and exogenous FGF21 plays an anti-apoptotic role in both in vitro and in vivo models, partially through the adiponectin signaling cascade (Joki et al 2015).…”

“…Under stress conditions, FGF21 has been shown to reduce the apoptosis of Islet b cells (Wente et al 2006), hepatocytes (Yu et al 2015), vascular cells (Wu et al 2014), cardiac endothelial cells (Lu et al 2010) and cardiomyocytes (Cong et al 2013, Liu et al 2013. Interestingly, FGF21 also protects the heart from apoptosis and remodeling through the activation of adiponectin release to activate the adiponectin signaling pathways (Joki et al 2015).…”

FGF21 as a mediator of adaptive responses to stress and metabolic benefits of anti-diabetic drugs

“…It has been reported that FGF21 was increased in the serum of human subjects with CAD and carotid artery plaques, and increased FGF21 levels were associated with adverse lipid profiles in CAD subjects (Lin et al 2010, Chow et al 2013. A recent study has shown that the serum FGF21 level was also increased in atherosclerosis-prone apolipoprotein E knockout (Apoe K/K ) mice fed an atherogenic diet (Wu et al 2014). FGF21 administration improved atherogenic diet-induced dyslipidemia and vascular atherosclerotic lesions in Apoe K/K mice, probably by mitigating ER stress, a contributing factor in the pathogenesis of atherosclerosis (Wu et al 2014).…”

Snapshots: Endoplasmic Reticulum Stress in Lipid Metabolism and Cardiovascular Disease

“…Macrophages are particularly vulnerable to lipidinduced toxicity; differentiation and recruitment of m a c r o p h a g e s t o p l a q u e s a c c e l e r a t e t h e development of atherosclerosis (Hotamisligil et al, 2008;Wu et al, 2015;Ren et al, 2017). Erbay and colleagues reported that mitigation of ERS with a chemical lipid chaperone (aP2) results in significant protection against dying lipotoxic macrophages and prevents atherosclerosis, while these effects are reversed in the aP2 knockout mouse.…”