title: SIRT1 inhibits inflammatory response partly through regulation of NLRP3 inflammasome in vascular endothelial cells.
abstract: Emerging evidence has indicated that vascular endothelial cells (ECs) not only form the barrier between blood and the vessel wall but also serve as conditional innate immune cells. Our previous study found that SIRT1, a class III histone deacetylase, inhibits the inflammatory response in ECs. Recent studies revealed that SIRT1 also participates in the modulation of immune responses. Although the NLRP3 inflammasome is known to be a crucial component of the innate immune system, there is no direct evidence demonstrating the anti-inflammatory effect of SIRT1 on ECs through the NLRP3 inflammasome. In this study, we observed that lipopolysaccharide (LPS) and adenosine triphosphate (ATP) triggered the activation of NLRP3 inflammasome in human umbilical vein ECs (HUVECs). Moreover, SIRT1 expression was reduced in HUVECs stimulated with LPS and ATP. SIRT1 activator inhibited the expression of monocyte chemotactic protein-1 (MCP-1) and C-reactive protein (CRP), whereas SIRT1 knockdown resulted in significant increases in MCP-1 and CRP levels in HUVECs stimulated with LPS and ATP. Importantly, the lack of SIRT1 enhanced NLRP3 inflammasome activation and subsequent caspase-1 cleavage. On the other hand, NLRP3 siRNA blocked the activation of the NLRP3 inflammasome in HUVECs stimulated with LPS plus ATP. Further study revealed that NLRP3 inflammasome blockade significantly reduced MCP-1 and CRP production in HUVECs. In vivo studies indicated that implantation of the periarterial carotid collar inhibited arterial SIRT1 expression in rabbits. Meanwhile, treatment with a SIRT1 activator decreased the expression levels of MCP-1 and CRP in collared arteries and the interleukin (IL)-1β level in serum. Taken together, these findings indicate that NLRP3 inflammasome activation promoted endothelial inflammation and that SIRT1 inhibits the inflammatory response partly through regulation of the NLRP3 inflammasome in ECs.
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Yanxiang
authors: Y
authors: Li
authors: Department of Obstetrics and Gynecology, Xi'an No. 4 Hospital, Xi'an, Shaanxi 710004, China.
authors: Ping
authors: P
authors: Wang
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Xiaofeng
authors: X
authors: Yang
authors: Laboratory Animal Center, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Weirong
authors: W
authors: Wang
authors: School of Pharmacy, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Jiye
authors: J
authors: Zhang
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Yanhao
authors: Y
authors: He
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Wei
authors: W
authors: Zhang
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Ting
authors: T
authors: Jing
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China.
authors: Bo
authors: B
authors: Wang
authors: Department of Pharmacology, Xi'an Jiaotong University, Health Science Center, Xi'an, Shaanxi 710061, China. Electronic address: linrong63@aliyun.com.
authors: Rong
authors: R
authors: Lin
mesh_terms: D000818:Animals; D015153:Blotting, Western; D042783:Endothelial Cells / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005455:Fluorescent Antibody Technique; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D008297:Male; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000276:immunology*; D011817:Rabbits; D060888:Real-Time Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000276:immunology*
chemical_list: D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Cytokines; Endothelial cells; Inflammation; NLRP3 inflammasome; SIRT1