title: Cadmium induces NLRP3 inflammasome-dependent pyroptosis in vascular endothelial cells.
abstract: Cadmium (Cd) is an important and common environmental pollutant that has been linked to cardiovascular diseases, such as atherosclerosis and hypertension. Increasing evidence demonstrates that Cd impairs the cardiovascular system by targeting vascular endothelial cells, but the underlying mechanisms remain obscure. In human umbilical vein endothelial cells (HUVECs), we observed that Cd treatment led to cell death and the generation of inflammatory cytokines. The Cd-induced cell death was identified as pyroptosis, a novel pro-inflammatory form of cell death depending on caspase-1 activation. In addition, exposure of HUVECs to Cd resulted in NLRP3 inflammasome activation as evidenced by cleavage of caspase-1 and downstream interleukin (IL)-1β production. Moreover, knockdown of NLRP3 by small interfering RNA efficiently suppressed Cd-induced caspase-1 cleavage, IL-1β production and pyroptosis in HUVECs. Additional experiments demonstrated that treatment with Cd significantly increased the levels of mitochondrial reactive oxygen species (mtROS) and intracellular ROS in HUVECs. Accordingly, pre-treatment with mtROS scavenger or total ROS scavenger reduced Cd-induced activation of NLRP3 inflammasome and pyroptotic cell death. Taken together, our data suggest that NLRP3 inflammasome, activated by the generation of mtROS, mediates Cd-induced pyroptosis in HUVECs. Our results provide novel insights into Cd-induced cytotoxicity and the underlying mechanism by which Cd induces endothelial injury.
authors.affiliation: Department of Cardiovasology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhengwang
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Qinlong
authors.initials: Q
authors.lastname: Ma
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Huifeng
authors.initials: H
authors.lastname: Pi
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Yiliang
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Cardiovasology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, Sichuan, China. Electronic address: hhxiang17@163.com.
authors.forename: Houxiang
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Occupational Health, Third Military Medical University, Chongqing 400038, China. Electronic address: lunazhou00@163.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D002104:Cadmium / Q000494:pharmacology*; D002352:Carrier Proteins / Q000502:physiology*; D020170:Caspase 1 / Q000502:physiology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D000069292:Pyroptosis; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species; D002104:Cadmium; D020170:Caspase 1
keywords: Cadmium; Cardiovascular disease; NLRP3 inflammasome; Pyroptosis; ROS; Vascular endothelial cells