Fibroblast growth factor 21 reverses high-fat diet-induced impairment of vascular function via the anti-oxidative pathway in ApoE knockout mice

Wen Pin Huang, Chi Yu Chen, Tzu Wen Lin, Chin Sung Kuo, Hsin Lei Huang, Po Hsun Huang*, Shing Jong Lin

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Circulating endothelial progenitor cells (EPCs), which function in vascular repair, are the markers of endothelial dysfunction and vascular health. Fibroblast growth factor 21 (FGF21), a liver-secreted protein, plays a crucial role in glucose homeostasis and lipid metabolism. FGF21 has been reported to attenuate the progression of atherosclerosis, but its impact on EPCs under high oxidative stress conditions remains unclear. In vitro studies showed that the β-klotho protein was expressed in cultured EPCs and that its expression was upregulated by FGF21 treatment. Hydrogen peroxide (H2O2)-induced oxidative stress impaired EPC function, including cell viability, migration and tube formation. Pretreatment with FGF21 restored the functions of EPCs after the exposure to H2O2. Administration of N(ω)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, inhibited the effects of FGF21 in alleviating oxidative injury by suppressing endothelial nitric oxide synthase (eNOS). In an in vivo study, the administration of FGF21 significantly reduced total cholesterol (TC) and blood glucose levels in apolipoprotein E (ApoE)-deficient mice that were fed a high-fat diet (HFD). Endothelial function, as reflected by acetylcholine-stimulated aortic relaxation, was improved after FGF21 treatment in ApoE-deficient mice. Analysis of mRNA levels in the aorta indicated that FGF21 increased the mRNA expression of eNOS and upregulated the expression of the antioxidant genes superoxide dismutase (SOD)1 and SOD2 in ApoE-deficient mice. These data suggest that FGF21 improves EPC functions via the Akt/eNOS/nitric oxide (NO) pathway and reverses endothelial dysfunction under oxidative stress. Therefore, administration of FGF21 may ameliorate a HFD-induced vascular injury in ApoE-deficient mice.

Original languageEnglish
Pages (from-to)2451-2461
Number of pages11
JournalJournal of Cellular and Molecular Medicine
Issue number8
StatePublished - Apr 2022


  • ApoE-deficient mice
  • endothelial nitric oxide synthase
  • endothelial progenitor cell
  • fibroblast growth factor 21
  • vascular function


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