SIRT3 overexpression antagonizes high glucose accelerated cellular senescence in human diploid fibroblasts via the SIRT3OXO1 signaling pathway

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• 作者：Bin Zhang (1) (2) (3)
  Shaoyuan Cui (1)
  Xueyuan Bai (1)
  Li Zhuo (4)
  Xuefeng Sun (1)
  Quan Hong (1)
  Bo Fu (1)
  Jianzhong Wang (1)
  Xiangmei Chen (1) (2)
  Guangyan Cai (1)
  
• 关键词：SIRT3 ; FOXO1 ; Human diploid fibroblasts ; High glucose ; Cellular senescence
• 刊名：AGE
• 出版年：2013
• 出版时间：December 2013
• 年：2013
• 卷：35
• 期：6
• 页码：2237-2253
• 全文大小：
• 作者单位：Bin Zhang (1) (2) (3)
  Shaoyuan Cui (1)
  Xueyuan Bai (1)
  Li Zhuo (4)
  Xuefeng Sun (1)
  Quan Hong (1)
  Bo Fu (1)
  Jianzhong Wang (1)
  Xiangmei Chen (1) (2)
  Guangyan Cai (1)
  
  1. State Key Laboratory of Kidney Diseases, Department of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, 100853, China
  2. School of Medicine, Nankai University, Tianjin, 300071, China
  3. Department of Nephrology, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
  4. Department of Nephrology, China - Japan Friendship Hospital, Beijing, 100029, China
  
• ISSN：1574-4647

文摘

Sirtuin 3 (SIRT3) is one of the seven mammalian sirtuins, which are homologs of the yeast Sir2 gene. SIRT3 is the only sirtuin reported to be associated with human life span. Many recent studies have indicated that SIRT3 levels are elevated by exercise and caloric restriction, but whether SIRT3 influences cell senescence under stressed conditions in human diploid fibroblasts has not been established. Our data showed that expression of SIRT3 is elevated in human diploid fibroblasts under low glucose (3.3mM glucose) growth conditions and decreased under high glucose (25mM glucose) growth conditions. We have demonstrated that SIRT3 interacts with forkhead box protein O1 (FOXO1). High glucose levels also increased aging phenotypes and FOXO1 acetylation level. We have demonstrated that overexpression of SIRT3 under high glucose conditions reduces FOXO1 acetylation, suggesting that deacetylation of FOXO1 by SIRT3 elevates the expression of the FOXO1 target genes, catalase, and manganese superoxide dismutase (MnSOD) while decreasing senescence phenotypes. We studied the effects of SIRT3 protein knockdown by shRNA under low glucose conditions. The data showed that shRNA-SIRT3 accelerated senescence phenotypes and acetylation of FOXO1; the expression level of catalase and MnSOD decreased compared with the control group. As a consequence, SIRT3 antagonized cellular senescence with the characteristic features of delayed SA-gal staining, senescence-associated heterochromatin foci (SAHF) formation, and p16INK4A expression. These results demonstrate for the first time that SIRT3 overexpression antagonizes high glucose-induced cellular senescence in human diploid fibroblasts via the SIRT3OXO1 signaling pathway.