mTORC2 facilitates endothelial cell senescence by suppressing Nrf2 expression via the Akt/GSK-3β/C/EBPα signaling pathway

• 来源期刊: 中国药理学报（英文版）
• 关键词: mTORC2 vascular endothelium senescence Akt Nrf2
• 年，卷（期）: 2018,（12）
• 页码范围: 1837-1846
• 页数: 10页
• 语种: 英文

摘要

Vascular endothelial cell senescence is a leading cause of age-associated and vascular diseases.Mammalian target of rapamycin complex 2 (mTORC2) is a conserved serine/threonine (Ser/Thr) protein kinase that plays an important regulatory role in various cellular processes.However,its impact on endothelial senescence remains controversial.In this study we investigated the role and molecular mechanisms of mTORC2 in endothelial senescence.A replicative senescence model and H2O2-induced premature senescence model were established in primary cultured human umbilical vein endothelial cells (HUVECs).In these senescence models,the formation and activation of mTORC2 were significantly increased,evidenced by the increases in binding of Rictor (the essential component of mTORC2) to mTOR,phosphorylation of mTOR at Ser2481 and phosphorylation of Akt (the effector of mTORC2) at Ser473.Knockdown of Rictor or treatment with the Akt inhibitor MK-2206 attenuated senescence-associated β-galactosidase (β-gal) staining and expression of p53 and p21 proteins in the senescent endothelial cells,suggesting that mTORC2/ Akt facilitates endothelial senescence.The effect of mTORC2/Akt on endothelial senescence was due to suppression of nuclear factor erythroid 2-related factor 2 (Nrf2) at the transcriptional level,since knockdown of Rictor reversed the reduction of Nrf2 mRNA expression in endothelial senescence.Furthermore,mTORC2 suppressed the expression of Nrf2 via the Akt/GSK-3β/C/EBPα signaling pathway.These results suggest that the mTORC2/Akt/GSK-3β/C/EBPα/Nrf2 signaling pathway is involved in both replicative and inducible endothelial senescence.The deleterious role of mTORC2 in endothelial cell senescence suggests therapeutic strategies (targeting mTORC2) for aging-associated diseases and vascular diseases.