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Sirt-1 is required for the inhibition of apoptosis and inflammatory responses in human tenocytes.

Busch, F, Mobasheri, A, Shayan, P, Stahlmann, R and Shakibaei, M (2012) Sirt-1 is required for the inhibition of apoptosis and inflammatory responses in human tenocytes. J Biol Chem, 287 (31). pp. 25770-25781.

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Tendon overuse injuries and tendinitis are accompanied by catabolic processes and apoptosis of tenocytes. However, the precise molecular mechanisms of the destructive processes in tendon are not fully understood. Sirt-1, a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase, has been linked to transcriptional silencing and appears to play a key role in inflammation. The purpose of this study was to examine whether down-regulation of Sirt-1 using antisense oligonucleotides (ASO) affects inflammatory and apoptotic signaling in tenocytes. Transient transfection of tenocytes with ASO against Sirt-1 induced expression of Bax and other proteins involved in apoptosis (cleaved caspase-3 and poly(ADP-ribose)polymerase), acetylation of tumor suppressor p53, and mitochondrial degradation. Interestingly, Sirt-1 was found to interact directly with p53. In contrast, Sirt-1 activator resveratrol inhibited interleukin-1β (IL-1β)- and nicotinamide-induced NF-κB activation and p65 acetylation and suppressed the activation of IκB-α kinase. Resveratrol also reversed the IL-1β- or nicotinamide-induced up-regulation of various gene products that mediate inflammation (cyclooxygenase-2) and matrix degradation (matrix metalloproteinase-9) that are known to be regulated by NF-κB. Knockdown of Sirt-1 by using ASO abolished the inhibitory effects of resveratrol on inflammatory and apoptotic signaling including Akt activation and SCAX suppression. Down-regulation of histone deacetylase Sirt-1 by mRNA interference abrogated the effect of resveratrol on NF-κB suppression, thus highlighting the crucial homeostatic role of this enzyme. Overall, these results suggest for the first time that Sirt-1 can regulate p53 and NF-κB signaling via deacetylation, demonstrating a novel role for resveratrol in the treatment of tendinitis/tendinopathy.

Item Type: Article
Divisions : Surrey research (other units)
Authors :
Busch, F
Shayan, P
Stahlmann, R
Shakibaei, M
Date : 27 July 2012
DOI : 10.1074/jbc.M112.355420
Uncontrolled Keywords : Acetylation, Apoptosis, Caspase 3, Cell Proliferation, Cell Survival, Cells, Cultured, Enzyme Activation, Enzyme Activators, Gene Knockdown Techniques, Humans, Interleukin-1beta, Mitochondria, NF-kappa B, Poly(ADP-ribose) Polymerases, Protein Binding, Protein Processing, Post-Translational, Proteolysis, Proto-Oncogene Proteins c-akt, RNA Interference, RNA, Small Interfering, Signal Transduction, Sirtuin 1, Stilbenes, Tendinopathy, Tendons, Tumor Suppressor Protein p53, bcl-2-Associated X Protein
Related URLs :
Depositing User : Symplectic Elements
Date Deposited : 17 May 2017 10:11
Last Modified : 24 Jan 2020 18:40

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