PMID- 34233231
OWN - NLM
STAT- MEDLINE
DCOM- 20220124
LR  - 20240226
IS  - 1878-1705 (Electronic)
IS  - 1567-5769 (Linking)
VI  - 99
DP  - 2021 Oct
TI  - SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular 
      endothelial cells.
PG  - 107926
LID - S1567-5769(21)00562-2 [pii]
LID - 10.1016/j.intimp.2021.107926 [doi]
AB  - Emerging evidence suggests that inflammation plays a pivotal role in 
      Atherosclerosis. Sirtuin 6 (SIRT6), a member of NAD(+)-dependent protein lysine 
      deacylases of the sirtuin family, plays an important role in the regulation of 
      metabolism, aging and stress resistance. However, the role of SIRT6 in vascular 
      inflammation and its molecular mechanism is unknown. The present study showed 
      that TNF-alpha significantly reduced the expression of SIRT6 protein and mRNA in a 
      concentration- and time-dependent manner and increased the expression of monocyte 
      chemotactic protein 1 (MCP-1), interleukin (IL) -6 and IL-1beta in human umbilical 
      vein endothelial cells (HUVECs). Overexpression of SIRT6 but not its 
      catalytically inactive mutant inhibited TNF-alpha-induced expression of MCP-1, IL-6 
      and IL-1beta. Knockdown of SIRT6 significantly enhanced TNF-alpha-induced expression of 
      MCP-1, IL-6 and IL-1beta. Moreover, knockdown of SIRT6 reduced TNF-alpha-induced nuclear 
      factor erythroid 2 related factor 2 (NRF2) nucleus protein expression, whereas 
      knockdown of NRF2 significantly enhanced TNF-alpha-induced expression of MCP-1, IL-6 
      and IL-1beta. In addition, overexpression of SIRT6 increased NRF2 and its target 
      genes expression, and knockdown of SIRT6 decreased NRF2 and its target genes 
      expression. Meanwhile, knockdown of SIRT6 inhibited NRF2 nucleus protein 
      expression. Further, knockdown of SIRT6 decreased phosphorylation of NRF2, 
      overexpression of SIRT6 increased phosphorylation of NRF2. SIRT6 interacted with 
      NRF2. In vivo, the levels of TNF-alpha and IL-1beta were increased in the serum of 
      hyperlipidemia mice. Hyperlipidemia-induced production of MCP-1, IL-6 and IL-1beta 
      was significantly augmented in the endothelium specific SIRT6 knockout mice. In 
      contrast, the expression of NRF2 and its target genes was reduced. Taken 
      together, these results indicate that SIRT6 protects against vascular 
      inflammation via its deacetylase activity and the NRF2-dependent signaling 
      pathway.
CI  - Copyright (c) 2021 Elsevier B.V. All rights reserved.
FAU - He, Yanhao
AU  - He Y
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China; College of Life Sciences, Yantai University, 
      Yantai, 264005, China.
FAU - Yang, Guangde
AU  - Yang G
AD  - School of Pharmacy, Xi'an Jiaotong University, Health Science Center, Xi'an, 
      Shaanxi 710061, China.
FAU - Sun, Lijing
AU  - Sun L
AD  - Department of Pharmacy, Yantai Affiliated Hospital of Binzhou Medical University, 
      Yantai, Shandong 264100, China.
FAU - Gao, Hongqian
AU  - Gao H
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China.
FAU - Yao, Feng
AU  - Yao F
AD  - School of Pharmacy, Xi'an Jiaotong University, Health Science Center, Xi'an, 
      Shaanxi 710061, China.
FAU - Jin, Zhen
AU  - Jin Z
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China.
FAU - Zheng, Zihan
AU  - Zheng Z
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China.
FAU - Chen, Lifang
AU  - Chen L
AD  - Laboratory Animal Center, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China.
FAU - Wang, Weirong
AU  - Wang W
AD  - Laboratory Animal Center, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China.
FAU - Zheng, Nanbo
AU  - Zheng N
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China; Department of Pharmacy, Xi'an Central Hospital, 
      Xi'an, Shaanxi 710003, China. Electronic address: zhengnanbo@stu.xjtu.edu.cn.
FAU - Lin, Rong
AU  - Lin R
AD  - Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, 
      Xi'an, Shaanxi 710061, China. Electronic address: linrong@mail.xjtu.edu.cn.
LA  - eng
PT  - Journal Article
DEP - 20210704
PL  - Netherlands
TA  - Int Immunopharmacol
JT  - International immunopharmacology
JID - 100965259
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (Chemokine CCL2)
RN  - 0 (IL1B protein, human)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Interleukin-6)
RN  - 0 (NF-E2-Related Factor 2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.5.1.- (Sirtuins)
SB  - IM
MH  - Animals
MH  - Anti-Inflammatory Agents/*metabolism/pharmacology
MH  - Chemokine CCL2/metabolism
MH  - Gene Expression Regulation
MH  - Gene Knockdown Techniques
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Interleukin-1beta/metabolism
MH  - Interleukin-6/metabolism
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - NF-E2-Related Factor 2/genetics/*metabolism
MH  - Oxidative Stress
MH  - Signal Transduction
MH  - Sirtuins/*metabolism/pharmacology
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - Mice
OTO - NOTNLM
OT  - Endothelial cells
OT  - Inflammation
OT  - NRF2
OT  - SIRT6
EDAT- 2021/07/08 06:00
MHDA- 2022/01/27 06:00
CRDT- 2021/07/07 20:10
PHST- 2021/03/23 00:00 [received]
PHST- 2021/06/10 00:00 [revised]
PHST- 2021/06/24 00:00 [accepted]
PHST- 2021/07/08 06:00 [pubmed]
PHST- 2022/01/27 06:00 [medline]
PHST- 2021/07/07 20:10 [entrez]
AID - S1567-5769(21)00562-2 [pii]
AID - 10.1016/j.intimp.2021.107926 [doi]
PST - ppublish
SO  - Int Immunopharmacol. 2021 Oct;99:107926. doi: 10.1016/j.intimp.2021.107926. Epub 
      2021 Jul 4.