Therapeutic effects of fibroblast growth factor‑21 against atherosclerosis via the NF‑κB pathway

Abstract

Fibroblast growth factor-21 (FGF-21) is a pleiotropic protein predominantly secreted in the liver, adipose tissue and pancreas. It has been reported that the metabolic hormone effects of FGF-21 on energy metabolism are essential for human vascular endothelial cells. The aim of the present study was to investigate the therapeutic effects and the underlying primary mechanism of FGF-21 on atherosclerosis in a rat model induced by vitamin D3 and a high fat diet. The rats with atherosclerosis were randomly divided into vehicle (PBS; negative control), FGF-21 (6 mg/kg/d) and atorvastatin (6 mg/kg/d; positive control) groups (n=40 in each group). The rats with atherosclerosis received continuous drug or PBS administration via intravenous injection for a treatment period of 30 days, following which all animals were sacrificed. The expression levels of FGF-21 were determined prior to and following treatment with the drug or PBS. Alterations in ultrastructure and histopathology in vascular endothelial cells were examined, and the expression of nuclear transcription factor kappa B (NF-κB) and levels of blood lipids in the thoracic aorta tissues were also determined. The results showed that typical atheromatous plaques formed, and the mRNA and protein expression levels of FGF-21 were lower in the vascular endothelial cells of the rats with atherosclerosis, compared with the normal rats. FGF-21 significantly reduced blood lipids and glucose in the rats with atherosclerosis, compared with those in the PBS and atorvastatin groups (P<0.01). The expression levels of Rho kinase and NF-κB were significantly lower in the FGF-21 group, compared with the normal control group (P<0.01). Statistically significant differences were found in atheromatous plaques and inflammatory factors in the FGF-21 group, compared with the PBS and atorvastatin groups (P<0.01). In conclusion, FGF-21 significantly downregulated the levels of blood lipids, Rho kinase and NF-κB, which contributed to atherosclerosis therapy in the model rats and indicated the potential mechanisms against atherosclerosis in the model rats.

Adipokines and Inflammation: Focus on Cardiovascular Diseases

“…In ApoE −/− mice, FGF-21 treatment was described to mitigate atherosclerosis through the inhibition of NLRP3, the inhibition of factor-associated suicide (FAS) signalling, the reduction of cholesterol accumulation through the promotion of autophagy and by suppressing hepatic cholesterol synthesis, increasing adiponectin production by adipocytes, and attenuating endoplasmic-reticulum-stress-induced apoptosis [ 329 , 330 , 331 , 332 , 333 ]. In rats with atherosclerosis, FGF-21 decreases inflammation by increasing the signalling of nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) and by reducing the expression of NF-κB [ 334 , 335 ]. In diabetic mice, FGF-21 ameliorates endothelial dysfunction by suppressing oxidative stress and enhancing endothelium-dependent vasorelaxation through the activation of calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2)/protein kinase AMP-activated catalytic subunit alpha (AMPKα) [ 336 ].…”

Erchen Decoction Ameliorates Lipid Metabolism by the Regulation of the Protein CAV‐1 and the Receptors VLDLR, LDLR, ABCA1, and SRB1 in a High‐Fat Diet Rat Model

“…Moreover, atorvastatin (ATV) has been preferred over other satins initially due to its effective hypolipidemic effect. So it is widely used as a positive control to lower elevated lipid levels; in studies the dose of ATV for rats ranges from 2.08 to 20 mg/kg/day, but the most commonly used effective dose is 10 mg/kg/day [ 4 – 6 ]. However, statins cannot be applied to all populations worldwide due to side effects, whereas in certain cases their efficacy in lowering cholesterol level is not adequate [ 7 ].…”

Effects of interleukin-1 antagonism and corticosteroids on fibroblast growth factor-21 in patients with metabolic syndrome

“…FGF21 has proven anti-inflammatory action mediated via inhibition of the activation of nuclear factor-κB, almost similar to the effects of glucocorticoids 40 – 42 . Elevations of FGF21 in inflammatory states might therefore be counterregulatory.…”