title: SIRT3 overexpression antagonizes high glucose accelerated cellular senescence in human diploid fibroblasts via the SIRT3-FOXO1 signaling pathway.
abstract: 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 (3.3 mM glucose) growth conditions and decreased under high glucose (25 mM 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-β-gal staining, senescence-associated heterochromatin foci (SAHF) formation, and p16(INK4A) expression. These results demonstrate for the first time that SIRT3 overexpression antagonizes high glucose-induced cellular senescence in human diploid fibroblasts via the SIRT3-FOXO1 signaling pathway.
authors.affiliation: State Key Laboratory of Kidney Diseases, Department of Nephrology, Chinese PLA General Hospital and Military Medical Postgraduate College, Beijing, 100853, China, binzhang301@163.com.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Shaoyuan
authors.initials: S
authors.lastname: Cui
authors.forename: Xueyuan
authors.initials: X
authors.lastname: Bai
authors.forename: Li
authors.initials: L
authors.lastname: Zhuo
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Sun
authors.forename: Quan
authors.initials: Q
authors.lastname: Hong
authors.forename: Bo
authors.initials: B
authors.lastname: Fu
authors.forename: Jianzhong
authors.initials: J
authors.lastname: Wang
authors.forename: Xiangmei
authors.initials: X
authors.lastname: Chen
authors.forename: Guangyan
authors.initials: G
authors.lastname: Cai
mesh_terms: D000375:Aging / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000235:genetics*; D004171:Diploidy; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D047468:Immunoprecipitation; D007668:Kidney / Q000196:embryology / Q000378:metabolism; D008168:Lung / Q000196:embryology / Q000378:metabolism; D008856:Microscopy, Fluorescence; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D056566:Sirtuin 3 / Q000096:biosynthesis / Q000235:genetics*; D013549:Sweetening Agents / Q000494:pharmacology
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D013549:Sweetening Agents; D012313:RNA; C466093:SIRT3 protein, human; D056566:Sirtuin 3; D005947:Glucose