FGF21 attenuates high uric acid‑induced endoplasmic reticulum stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1

Abstract

Uric acid (UA) is the final oxidation product of purine metabolism. Hyperuricemia has been previously reported to contribute to vascular endothelial dysfunction and the development of cardiovascular diseases, metabolic syndrome and chronic kidney diseases. In addition, it has been reported that fibroblast growth factor 21 (FGF21) can exert regulatory effects on UA-induced lipid accumulation. Therefore, the present study aimed to investigate the possible role of FGF21 in HUVEC cell injury induced by UA. The study used UA to induce HUVEC cell injury, inhibited sirtuin 1 (Sirt1) expression using EX527 and overexpressed FGF21 by transfection. Subsequently, reverse transcription-quantitative PCR was performed to measure the mRNA expression levels of FGF21, Sirt1 and inflammatory cytokines TNF-α, IL-1β and IL-6, whereas western blotting was performed to measure their corresponding protein expression levels including FGF21, Sirt1, NLR family pyrin domain containing 3, pro-caspase1, apoptosis-associated speck-like protein containing a CARD, activating transcription factor 4, C/EBP homologous protein and eukaryotic initiation factor 2. Furthermore, dichloro-dihydro-fluorescein diacetate staining was performed to measure intracellular reactive oxygen species (ROS) generation in HUVECs. The levels of ROS and nitric oxide were also quantified using commercial assay kits. The results demonstrated that overexpression of FGF21 significantly inhibited UA treatment-induced endoplasmic reticulum (ER) stress, inflammation and oxidative stress in HUVECs. Furthermore, overexpression of FGF21 significantly activated Sirt1. The sirt1 inhibitor, EX527, significantly abrogated the suppressive effects of FGF21 overexpression on ER stress, inflammation and oxidative stress in UA-stimulated HUVECs. To conclude, results of the present study suggested that FGF21 may attenuate UA-induced ER stress, inflammation and vascular endothelial cell dysfunction by activating Sirt1. Therefore, FGF21 may be a potential effective target for the future treatment of vascular endothelial cell dysfunction.

Uric Acid Reacts with Peroxidasin, Decreases Collagen IV Crosslink, Impairs Human Endothelial Cell Migration and Adhesion

“…However, a hyperuricemic concentration, 600 µM, leads cells to senescence [ 69 ] and inhibition of migration [ 70 ]. Higher concentrations (720 µM) induced ER stress [ 71 , 72 ].…”

HDAC inhibitors alleviate uric acid-induced vascular endothelial cell injury by way of the HDAC6/FGF21/PI3K/AKT pathway.

“… 41 , 42 Overexpression of FGF21 in endothelial cells can reduce oxidative stress and improve endothelial function. 43 As for the role of FGF21 in UA-induced VECI, Rong and coworkers demonstrated that FGF21 could attenuate high UA-induced endothelial. 43 Our results demonstrated that FGF21 knockdown abrogated the suppressive effect of TSA on inflammatory factor release and ROS generation.…”

“… 43 As for the role of FGF21 in UA-induced VECI, Rong and coworkers demonstrated that FGF21 could attenuate high UA-induced endothelial. 43 Our results demonstrated that FGF21 knockdown abrogated the suppressive effect of TSA on inflammatory factor release and ROS generation. Moreover, FGF21 knockdown aggravated UA-induced endothelial dysfunction and endothelial–interstitial transformation.…”

Hyperuricemia: A key contributor to endothelial dysfunction in cardiovascular diseases

“…α‐Lipoic acid inhibited EC apoptosis and enhanced NO production in both in vitro and in vivo HUA models by attenuating oxidant stress and activating Akt signaling 113 . Fibroblast growth factor 21 (FGF21) attenuated ED induced by high levels of UA in HUVECs by activating Sirt1, which was manifested as the attenuation of oxidative stress, ER stress, and inflammation 70 . Collectively, although not an official recommendation, optimal pharmacological treatments might be an important approach to combat HUA‐induced ED.…”