Fibroblast growth factor 21 delayed endothelial replicative senescence and protected cells from H₂O₂-induced premature senescence through SIRT1.

Abstract

Vascular aging is an independent risk factor for age-related diseases, including atherosclerosis. Fibroblast growth factor 21 (FGF21) has been widely recognized as a metabolic regulator that is elevated in response to caloric and nutritional restrictions. Recent studies have demonstrated its emerging role as a pro-longevity hormone, but its effects on the senescence of human umbilical vascular endothelial cells (HUVECs) remain unclear. In the present study, we explored the anti-senescence effects and underlying mechanism of FGF21 on HUVECs. Co-cultivation of HUVECs with 5 ng/mL FGF21 significantly attenuated the phenotype changes of cells during <i>in vitro</i> subculture, including increased senescent population, decreased proliferation rate, decreased SIRT1 and elevated P53 and P21 protein levels. FGF21 also protected HUVECs from H₂O₂-induced cell damage, including premature cell senescence, intracellular accumulation of reactive oxygen species, increased DNA damage, decreased SIRT1 protein level and elevated protein levels of VCAM-1, ICAM-1, P53 and P21. Transient knockdown of <i>SIRT1</i> in HUVECs significantly suppressed the protective effects of FGF21 for the rescue of H₂O₂-induced premature senescence and DNA damage, which suggests that the anti-senescence effect of FGF21 on HUVECs is SIRT1-dependent. These results support the potential of FGF21 as a therapeutic target for postponing vascular aging and preventing age-related vascular diseases.