Sirt-1 Is Required for the Inhibition of Apoptosis and Inflammatory Responses in Human Tenocytes

Abstract

Background: Sirt-1 has been linked to transcriptional silencing and appears to play a key role in inflammation. Results: Transfection of tenocytes with antisense oligonucleotides against Sirt-1-induced inflammation and apoptosis. Conclusion: Sirt-1 can regulate p53 and NF-B activity via deacetylation. Significance: Down-regulation of Sirt-1 by mRNA interference abrogated the effect of resveratrol on p53 and NF-B suppression.

Sirtuin-1 (SIRT1) Is Required for Promoting Chondrogenic Differentiation of Mesenchymal Stem Cells

“…Interestingly, MSC derived from SIRT1 knock-out mice showed clearly reduced chondrogenic potential in vitro (67). Indeed, these results are consistent with earlier reports demonstrating that SIRT1 is able to interact with other transcription factors, like Runx2 in osteoblasts or scleraxis in tenocytes (38,62,68) or p53, NF-B, myogenic differentiation, high mobility group I, E2F transcription factor, peroxisome proliferator-activated receptor-␥, and forkhead box O (27,28,30,69).…”

“…Furthermore, our laboratory and others have previously reported that resveratrol is an inhibitor of the pro-inflammatory cytokine IL-1␤, highlighting that resveratrol suppressed IL-1␤-induced activation of NF-B and NF-B-dependent gene products (51,57,58). Indeed, we have also shown that resveratrol inhibited IL-1␤-induced apoptosis in tenocytes, and this was linked to changes in the expression of p53, Bax, and caspase-3 (38). However, the mechanisms regulating the suppressive signaling of resveratrol on IL-1␤-induced NF-B transcriptional activity have not yet been fully understood.…”

“…Moreover, these findings strongly indicate that downregulation of SIRT1 by mRNA interference abrogates its suppressive effects on NF-B, indicating the essential role and function of SIRT1 for chondrogenic differentiation and survival of MSC. Furthermore, several reports have shown that SIRT1 deacetylates lysine residues of histone proteins and other nuclear proteins and transcription factors linked with apoptosis and inflammation, such as p53 (38,63) and NF-B subunit p65 (38,64), thereby regulating transcriptional activity of target proteins. Interestingly, it has been reported that deacetylation of NF-B by SIRT1 suppresses DNA binding that leads to a loss of transactivation potential (45).…”

“…Antisense and Lipofectin-mediated Transfection-Transient transfection of primary human chondrocytes, chondrogenic differentiated MSCs, and MSCs undergoing chondrogenesis was performed as described previously (38). Phosphorothioated antisense oligonucleotide derived from mRNA nucleotide sequence of sirtuin-1 gene (SIRT1-ASO) (sequence 5Ј-GTAT-TCCACATGAAACAGACA-3Ј) and control sense oligonucleotides (SIRT1-SO) (sequence 5Ј-TGTCTGTTTCATGTG-GAATAC-3Ј) used in the experiments were synthesized by Eurofins (MWG/Operon, Ebersberg, Germany).…”

Sirtuin 1 inhibition delays cyst formation in autosomal-dominant polycystic kidney disease

“…During cyst development, TNF-α is secreted into cyst fluid via an uncertain mechanism, which as a secondary event further stimulates the expression of SIRT1 through TNF-α-mediated NF-κB activation. SIRT1 has been shown to suppress NF-κB activity through deacetylating p65 in different cell lines, which inhibits the inflammation induced by NF-κB (45)(46)(47). Whether there is a feedback loop between SIRT1 expression and NF-κB activation in cystic epithelial cells and whether TNF-α signaling is able to override the inhibition of SIRT1 on NF-κB will require further investigation.…”