Fibroblast Growth Factor 21 Protects Against High Glucose Induced Cellular Damage and Dysfunction of Endothelial Nitric-Oxide Synthase in Endothelial Cells

Abstract

Aims: Fibroblast growth factor 21 (FGF21) is a powerful endocrine hormone modulating glucose and lipid metabolism and represents a promising drug for type 2 diabetes. The present study was to determine the effect of FGF21 on high glucose-induced damage and dysfunction in endothelial cells. Methods: The protein expression of β-klotho was examined in human umbilical vein endothelial cell (HUVECs) using immunofluorescence and Western blotting. HUVECs were cultured in medium with normal glucose (NG), high glucose (HG) and HG + FGF21 (30 nM). Cell viability, migration, reactive oxygen species (ROS), malondialdehyde (MDA), superoxide dismutase, nitric oxide (NO) production, intracellular cyclic guanosine monophosphate (cGMP) and endothelial nitric oxide synthase (eNOS) phosphorylation at Ser-1177/Ser-633 sites were measured. Results: β-klotho, the anchor protein of FGF21, is expressed in HUVECs. Administration of FGF21 prevented HG-induced impairment of cell viability, migration, oxidant stress, NO production and intracellular cGMP levels in HUVECs. FGF21 also rescued HG-induced decrease of eNOS phosphorylation at Ser-1177 and Ser-633. HG and FGF21 had no effects on eNOS phosphorylation at Ser-617 and Thr-495. Inhibition of AMP-activated protein kinase (AMPK), but not Akt or Ca²⁺/calmodulin-dependent protein kinase II, abolished the protective effect of FGF21 on eNOS phosphorylation at Ser-1177. The protective effect of FGF21 on eNOS phosphorylation at Ser-633 was also abolished by inhibition of AMPK but not by Akt or cAMP-dependent protein kinase A. Conclusion: Our results provide the first evidence that FGF21 protects against high glucose induced cell damage and eNOS dysfunction in an AMPK-dependent manner in HUVECs, and suggest that FGF21 may be a promoting therapeutic agent for vascular complications in diabetes.

Induction of Haemeoxygenase-1 Directly Improves Endothelial Function in Isolated Aortas from Obese Rats through the Ampk-Pi3k/Akt-Enos Pathway

“…It is known that impaired EDV in obese rats arises from decreased production and/ or bioactivity of NO induced by eNOS phosphorylation [15,27]. In the present study, we found that induction of HO-1 with CoPP significantly enhanced eNOS phosphorylation and total production of NO by thoracic aortic rings compared with that by rings from obese rats without CoPP pre-incubation.…”

Anti-inflammatory effects of exercise training in adipose tissue do not require FGF21

“…While FGF21KO-SED WAT and BAT had a more pro-inflammatory phenotype compared to WT-SED mice, it is unclear if that was a direct effect of FGF21 ablation, or secondary to the increase in adiposity observed in the KO mice. However, emerging data suggest a direct role for FGF21 in alleviating ER stress and inflammation (Guo, et al 2016; Wang, et al 2014; Yu et al 2016). In order to interrogate further whether the inflammatory changes observed in the KO mice were dependent or independent of the increase in adiposity, we statistically adjusted for the effect of body weight on all inflammatory outcomes (Supplementary Table 1).…”

“…Whereas lean adipose tissue is characterized by the absence of inflammation and increased mitochondrial function (Flachs, et al 2013), obese/sedentary adipose tissue is typified by a pro-inflammatory phenotype and impaired mitochondrial activity (Okamoto, et al 2007). Meanwhile, exercise improves WAT mitochondrial content and function (Stanford et al 2015; Wang et al 2014), and reports have implicated FGF21 in mediating mitochondrial biogenesis via regulation of Pgc1alpha (Okamoto et al 2007; Stanford et al 2015). Thus, mitochondria-related markers were assessed in WAT and BAT to determine the potential impact of loss of FGF21 on the ability of exercise to affect these parameters.…”

Fibroblast Growth Factor 21 As an Emerging Therapeutic Target for Type 2 Diabetes Mellitus

“…β‐klotho is enriched in the liver, white (WAT) and brown adipose tissues (BAT), the pancreas, and the central nervous system (CNS), which critically modulates glucose and lipid homeostasis. In addition, β‐klotho has been recently detected in other tissues such as placenta, human umbilical vein endothelial cells, and endothelial cells; in which FGF21 has been suggested to regulate the local metabolism in those tissues.…”