Sirtuin 1 Suppresses Hydrogen Peroxide‐Induced Senescence and Promotes Viability and Migration in Lens Epithelial Cells by Inhibiting Forkhead Box Protein O1/Toll‐Like Receptor 4 Pathway
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ABSTRACT Age‐related cataracts (ARCs) are associated with increased oxidative stress and cellular senescence. Our objective is to investigate the function of Sirtuin 1 (SIRT1) within ARCs. In ARCs tissues and H 2 O 2 ‐treated lens epithelial cells (LECs), the expression levels of SIRT1 were examined. Senescence‐associated β‐galactosidase (SA‐β‐gal) staining was employed to evaluate cellular senescence. The Cell Counting Kit‐8 assay was employed to measure viability. A wound healing assay was performed to assess migratory capacity in LECs. Oxidative stress‐related indicators were determined by enzyme‐linked immunosorbent assay kits. Additionally, the Coxpresdb and GeneCards databases were utilized to identify downstream pathways of SIRT1 in ARCs. The expression levels of protein and mRNA were detected using western blot and real‐time quantitative polymerase chain reaction, respectively. The expression of SIRT1 was downregulated in ARCs tissues with an increase in reactive oxygen species. In H 2 O 2 ‐induced LECs, SIRT1 was downregulated and its overexpression inhibited oxidative stress and cellular senescence while promoting viability and migration. Furthermore, FoxO1/TLR4 pathway was screened out as the key pathway of SIRT1, which was activated in H 2 O 2 ‐induced LECs senescence. Overexpression of SIRT1 suppressed FoxO1/TLR4 pathway. Further research demonstrated that the activation of FoxO1/TLR4 pathway reversed the inhibitory role of SIRT1 in oxidative stress‐induced cellular senescence and the promotion effect of SIRT1 on viability and migration in H 2 O 2 ‐induced LECs. SIRT1 inhibits oxidative stress‐induced cellular senescence and promotes the viability and migration in H 2 O 2 ‐induced LECs via suppressing FoxO1/TLR4 pathway.Keywords:
Senescence
Viability assay
Sirtuin 1
FOXO1
Sirtuin is a type of deacetylase acted on histone. Sirtuin 1 （SIRT1） is the most homologous to the homologue of silent information regulator 2 （SIR2） in mammals. Its main function is to regulate the body energy metabolism, cell senescence and response to stress. SIRT1 inhibits apoptosis through the interaction of several transcription factors involving in stress response. It is a neuroprotective agent.
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sirtuin; neuroprotective agents; apoptosis
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【目的】Sirtuin-1（SIRT1）はヒストン脱アセチル酵素であり，神経保護や脂質代謝などへの関与が報告されている．本研究ではヒト単球のIL-10制御におけるSIRT1の役割を検討した．【方法】健常者末梢血から精製した単球を用いLPSまたはIFNβで刺激後にSIRT1遺伝子発現を定量した．健常者，無治療multiple sclerosis（MS）患者，IFNβ治療MS患者の単球におけるSIRT1発現を定量した．単球のIL-10産生に対するresveratrol（SIRT1活性化剤），EX527（同抑制剤）の作用を検討した．【結果】単球におけるSIRT1発現はLPSで低下した一方，IFNβで上昇した．単球におけるSIRT1発現に健常者と無治療MS患者間で差は確認できなかったが，IFNβ治療患者で無治療患者より高い傾向が見られた．ResveratrolはLPS刺激に対する単球のIL-10産生を増強した．IFNβは単球からのIL-10産生を増強したが，この作用はEX527によりキャンセルされた．【結論】SIRT1は単球のIL-10制御に関与しており，IFNβによるIL-10産生増強にも関与することが示唆された．SIRT1は神経変性疾患動物モデルにおいて神経保護作用が報告されており，神経と免疫双方が関与する疾患であるMSにとって有用な治療標的であると予想される．
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Sirtuin 1, a member of sirtuin family of histone deacetylase enzymes, has been implicated in a variety of physiologic and pathologic events, including energy metabolism, cell survival, and age-related alterations. In view of the anti-inflammatory properties of sirtuin 1 along with its protective role in ischemia reperfusion injury, it might be considered as contributing to the promotion of transplantation outcome. However, the potential ability of sirtuin 1 to induce malignancies raises some concerns about its overexpression in clinic. Moreover, despite the findings of sirtuin 1 implication in thymic tolerance induction and T regulatory (Treg) cells survival, there is also evidence for its involvement in Treg suppression and in T helper 17 cells differentiation. The identification of sirtuin 1 natural and synthetic activators leads to the proposal of sirtuin 1 as an eligible target for clinical interventions in transplantation. All positive and negative consequences of sirtuin 1 overactivation/overexpression in the allograft should therefore be studied thoroughly. Herein, we summarize previous findings concerning direct and indirect influences of sirtuin 1 manipulation on transplantation.
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Nicotinamide mononucleotide
Nicotinamide phosphoribosyltransferase
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SIRT2
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Atherosclerosis is the commonest cause of death in the world and one of the most important processes that occurs with increasing age because it is accompanied by progressive endothelial dysfunction. Recent studies demonstrated that Sirtuin 1 (SIRT1) might potentially affect cell senescence. However, the effect of SIRT1 on the regulation of human umbilical vein endothelial cell (HUVEC) senescence with total flavonoids (TFs) has not been addressed previously. This study investigated how SIRT1 functions in the process of HUVEC senescence when TFs are present and identified the potential molecular mechanisms involved. Using a model of HUVEC senescence induced by angiotensin II, TFs pretreatment reduced the percentage of senescence-associated β -galactosidase (SA- β -gal) cells and p53 mRNA expression. The level of SIRT1 protein and E2F1 decreased during HUVEC senescence and could be partially recovered when cells were coincubated with TFs, while the levels of proteins p53 and p21 increased during cell senescence and diminished in response to the TFs treatment. When coincubated with 20 mM nicotinamide, the results with SA- β -gal-positive cells and the expression of SIRT1, E2F1, p53, and p21 were contrary to that obtained with only TFs pretreatment. The data indicate that the TFs exert their effect on HUVEC senescence through SIRT1.
Senescence
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Sirtuin 1
Calorie Restriction
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SirT1 is a deacetylase whose expression and activity increases during times of caloric restriction (CR). CR has been implicated lifespan extension in rodents, flies and worms, and SirT1 appears to be required for this increased longevity. Sirtuins have also been implicated in the regulation of transcriptional events, apoptosis, and energy efficiency. Many of the sirtuin proteins are similar in function, although they vary in cellular location. Interestingly, numerous studies demonstrated SirT1 activity during CR, but CR effects on the remaining six sirtuin proteins remains relatively unknown. This study aims to analyze the expression of sirtuins in a variety of tissues from mice subjected to a two week 60% CR. We hypothesize that CR will cause increases in mRNA levels of multiple sirtuins. Male and female mice were monitored daily to determine their individual food intake for two weeks and were then given 60% of their normal daily intake for two weeks. Animals were euthanized and tissues snap frozen and stored until further processing. We will present data showing the levels of SirT1–7 as well as other important metabolic and reproductive genes in response to CR. This work is supported by NIH grants U54 HD012303 and T32 DK007494.
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Sirtuin 단백질들은 주로 노화과정을 조절하는 역할을 하는 것으로 알려져 있으며, 다양한 생물학적인 성장과정에 지속적으로 관여하는 것으로 알려져 있다. 이들은 암, 신경퇴행성질환 심혈관계 질환들 등, 노화와 관련된 질환들의 발생을 일차적으로 방어하는 것으로 알려져 있다. 또한 유전적인 안정성을 조절하는데 중요하기 때문에 암 발생을 조절하는데 매우 유용할 것으로 생각하고 있다. 이번 연구에서 분화가 안되어 있는 지방줄기세포에 암을 유발하는 비유전독성화합물인 clonidine과 유전독성화합물인 2-nitrofluorene를 발암물질을 투여하여 세포의 성장을 관찰하였고, 지방줄기세포에 일정시간 처리한 후 지방줄기세포에서 시간에 따른 sirtuin 유전자의 발현을 관찰하고 세포의 증식과 비교하였다. 독성화합물을 처리한 사람의 지방줄기세포에서 SIRT1, 2, 3, 그리고 7 mRNA의 발현은 48시간 이후 증가하였으며, SIRT의 종류에 따라 증가 시기는 차이가 났다. 독성화합물을 처리한 지방줄기세포에서 SIRT1, 2, 3, 그리고 7 mRNA의 발현은 처리 96시간이 지나면 처리 전 세포의 발현 수준으로 감소하였다. 이 연구를 통해 지방줄기세포는 유전독성화합물인 2-nitrofluorene의 투여는 지방줄기세포의 성장에 저해를 일으켰다. 발암물질을 투여한 후 시간에 따른 sirtuin1, 2, 3, 7 mRNA의 발현 변화는 유전독성 혹은 비유전독성 발암물질의 종류에 관계 없이 유사하게 관찰되었다. 즉 발암물질은 지방줄기세포에서 투여 초기에 sirtuin mRNA의 발현을 유도한다는 것을 알 수 있다. 이 연구 결과는 독성화합물에 의한 지방줄기세포의 성장 억제와 sirtuin의 세포 방어 기전에 대한 가능성을 제시한다.
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Abstract Mammalian ovarian follicular development is an intricate, elaborate, and well‐organized phenomenon regulated by various signaling pathways; however, the underlying mechanism remains unclear. Mammalian sirtuins (sirtuin 1 to sirtuin 7) are a group of NAD + ‐dependent deacetylases implicated in various physiological processes including cell proliferation, apoptosis, cell cycle progression, and insulin signaling. Mammalian ovarian sirtuins have been studied using adult and aged bovine, porcine, and murine models. However, limited information is available regarding their precise expression patterns and the localization of follicle development in mice. This study aimed to assess the dynamic expression and localization of all seven sirtuins in early postnatal mouse ovaries through real‐time polymerase chain reaction analysis and immunohistochemistry, respectively. During postnatal ovarian follicle development, sirtuin 1, sirtuin 4, and sirtuin 6 were downregulated compared with those in 1‐day postnatal mouse ovaries ( p < .05), indicating that these three sirtuin genes may be markers of follicular development. Combining their localization in granulosa cells through immunohistochemical studies, sirtuin 1, sirtuin 4, and sirtuin 6 are suggested to play negative regulatory roles in mammal ovarian follicular granulosa cell development. Furthermore, we found that sirtuin 2 ( p < .05) and sirtuin 7 ( p < .05) mRNA were constantly upregulated relative to sirtuin 1, although limited information is available regarding sirtuin 7. Among all sirtuins in mouse ovaries, sirtuin 1 was relatively and steadily downregulated. Upon sirtuin 1 overexpression in 1‐day postnatal mouse ovaries via sirtuin 1‐harboring adenoviruses in vitro, the emergence of primary follicles was delayed, as was the emergence of secondary follicles in 4‐day postnatal ovaries. Further studies on KGN cell lines reported that interfering with sirtuin 1 expression in granulosa cell significantly affected granulosa cell proliferation and the expression of mitochondrial genes. This study presents the first systemic analysis of dynamic patterns of sirtuin family expression in early postnatal mice ovaries, laying the foundation for further studies on less discussed sirtuin subtypes, such as sirtuin 5 and sirtuin 7.
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OBJECTIVE The glucoincretin hormone glucagon-like peptide 1 (GLP-1) enhances glucose-stimulated insulin secretion and stimulates pancreatic β-cell mass expansion. We have previously shown that the forkhead transcription factor FoxO1 is a prominent transcriptional effector of GLP-1 signaling in the β-cell. FoxO1 activity is subject to a complex regulation by Akt-dependent phosphorylation and SirT1-mediated deacetylation. In this study, we aimed at investigating the potential role of SirT1 in GLP-1 action. RESEARCH DESIGN AND METHODS FoxO1 acetylation levels and binding to SirT1 were studied by Western immunoblot analysis in INS832/13 cells. SirT1 activity was evaluated using an in vitro deacetylation assay and correlated with the NAD+-to-NADH ratio. The implication of SirT1 in GLP-1–induced proliferation was investigated by BrdU incorporation assay. Furthermore, we determined β-cell replication and mass in wild-type and transgenic mice with SirT1 gain of function after daily administration of exendin-4 for 1 week. RESULTS Our data show that GLP-1 increases FoxO1 acetylation, decreases the binding of SirT1 to FoxO1, and stunts SirT1 activity in β-INS832/13 cells. GLP-1 decreases both the NAD+-to-NADH ratio and SirT1 expression in INS cells and isolated islets, thereby providing possible mechanisms by which GLP-1 could modulate SirT1 activity. Finally, the action of GLP-1 on β-cell mass expansion is abolished in both transgenic mice and cultured β-cells with increased dosage of SirT1. CONCLUSIONS Our study shows for the first time that the glucoincretin hormone GLP-1 modulates SirT1 activity and FoxO1 acetylation in β-cells. We also identify SirT1 as a negative regulator of β-cell proliferation.
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