title: SIRT1 Regulates the Inflammatory Response of Vascular Adventitial Fibroblasts through Autophagy and Related Signaling Pathway.
abstract: OBJECTIVE
  Autophagy is a lysosomal degradation pathway that is essential for cellular survival, differentiation, and homeostasis. Sirtuin 1 (SIRT1), a NAD+-dependent deacetylase, plays a pivotal role in modulation of autophagy. Recent studies found that autophagy was involved in the regulation of inflammatory response. In this study, we aimed to determine the effect of SIRT1 on autophagy and inflammation, and whether autophagy can regulate the inflammatory response in vascular adventitial fibroblasts (VAFs).
  
  
  METHODS
  Cell autophagy was evaluated by fluorescence microscope and transmission electron microscopy. The expression of protein and mRNA were determined by Western blot analysis and real time-PCR. The production of cytokine was detected by ELISA.
  
  
  RESULTS
  TNF-α induced autophagy and increased SIRT1 expression in VAFs. SIRT1 activator resveratrol enhanced TNF-α-induced VAF autophagy. In contrast, SIRT1 knockdown attenuated VAF autophagy. Both the Akt inhibitor MK2206 and mTOR inhibitor rapamycin further increased TNF-α-induced VAF autophagy. Furthermore, SIRT1 knockdown increased Akt phosphorylation and inhibited the autophagy in VAFs. However, MK2206 attenuated the effect of SIRT1 knockdown on VAF autophagy. In addition, ingenuity pathway analysis showed that there is a relationship between cell autophagy and inflammation. We found that SIRT1 knockdown increased the expression of NLRP3 and interleukin (IL)-6 and promoted the production of IL-1β in VAFs. Further study showed that autophagy activation decreased the expression of NLRP3 and IL-6 and inhibited the production of IL-1β, whereas autophagy inhibition increased the inflammatory response of VAFs. More importantly, our study showed that autophagy was involved in the degradation of NLRP3 through the autophagy-lysosome pathway.
  
  
  CONCLUSIONS
  SIRT1 not only regulates VAF autophagy through the Akt/mTOR signaling pathway but also suppresses the inflammatory response of VAFs through autophagy.
authors.forename: Wei-Rong
authors.initials: WR
authors.lastname: Wang
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Li
authors.forename: Ting
authors.initials: T
authors.lastname: Jing
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Li
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Yang
authors.forename: Yan-Hao
authors.initials: YH
authors.lastname: He
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Rong
authors.initials: R
authors.lastname: Lin
authors.forename: Ji-Ye
authors.initials: JY
authors.lastname: Zhang
mesh_terms: D063194:Adventitia / Q000166:cytology; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D053583:Interleukin-1beta / Q000032:analysis; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001549:Benzamides; D006575:Heterocyclic Compounds, 3-Ring; D053583:Interleukin-1beta; D015850:Interleukin-6; C548887:MK 2206; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009284:Naphthols; D034741:RNA, Small Interfering; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; C439060:sirtinol; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D056564:Sirtuin 1; D000077185:Resveratrol; D020123:Sirolimus
keywords: Akt/mTOR; Autophagy; Inflammation; SIRT1; Vascular adventitial fibroblasts