Glucose restriction delays senescence and promotes proliferation of HUVECs via the AMPK/SIRT1-FOXA3-Beclin1 pathway.

Abstract

Caloric restriction (CR) is an important means to delay senescence, and glucose restriction is one of the measures to achieve CR. On the basis of our previous work and bioinformatics analysis, we hypothesized that glucose restriction can up-regulate autophagy, inhibit senescence and promote proliferation via the AMPK/SIRT1-FOXA3-Beclin1 pathway in human umbilical vein endothelial cells (HUVECs). We found that compared with 5.5mmol/L and 25mmol/L glucose, 2.5mmol/L glucose restriction significantly reduced senescence, enhanced autophagy, increased migration speed, relieved G0/G1 phase arrest and enhanced proliferation of HUVECs. Furthermore, glucose restriction up-regulated AMPKα1, SIRT1, FOXA3 and Beclin1 expression in HUVECs. Additionally, we demonstrated that AMPKα1 phosphorylated FOXA3 at S170 and S305 in the cytoplasm and promoted FOXA3 nuclear translocation under glucose restriction. FOXA3 in the nucleus was deacetylated by SIRT1 at K214 and K221. Deacetylated FOXA3 specifically bound to +109 C in the Beclin1 transcriptional regulatory region, and significantly enhanced Beclin1 transcription and expression. siRNA knock down of AMPKα1, SIRT1, FOXA3 or Beclin1 expression impaired the glucose restriction-induced inhibition of senescence, enhanced autophagy, increased migration, and induced proliferation of HUVECs. This study confirmed that glucose restriction can enhance autophagy, inhibit senescence, and enhance proliferation of HUVECs through the AMPK/SIRT1-FOXA3-Beclin1 pathway.