title: P2X7R is involved in the progression of atherosclerosis by promoting NLRP3 inflammasome activation.
abstract: Purinergic 2X7 receptor (P2X7R) and nucleotide‑binding oligomerization domain-like receptor protein 3 (NLRP3) are expressed in macrophages in atherosclerotic lesions. However, the mechanisms through which P2X7R participates in the inflammatory response in atherosclerosis remain largely unknown. The aim of the present study was to investigate the role of P2X7R in atherosclerosis and the mechanisms of action of the NLRP3 inflammasome following stimulation with oxidized low-density lipoprotein (oxLDL). We observed the expression and distribution of P2X7R in the atherosclerotic plaque in the coronary arteries from an autopsy specimen and in that of the aortic sinuses of apoE(-/-) mice by immunohistochemistry and immunofluorescence staining. The specificity of short interfering RNA (siRNA) was used to suppress P2X7R and NLRP3 mRNA expression. RT-qPCR and western blot analysis were used to analyze mRNA and protein expression, respectively. Co-immunoprecipitation was used to examine the interaction between protein kinase R (PKR) phosphorylation and NLRP3. P2X7R and NLRP3 were expressed at high levels in the atherosclerotic plaque in the coronary arteries. Stimulation with oxLDL upregulated P2X7R, NLRP3 and interleukin (IL)-1β expression. P2X7R knockdown by siRNA suppressed NLRP3 inflammasome activation by inhibiting the PKR phosphorylation mediated by oxLDL. In the atherosclerotic lesions in the aortic sinuses of apoE(-/-) mice, P2X7R expression was found at high levels. Moreover, P2X7R siRNA attenuated the development of atherosclerosis in the apoE(-/-) mice. In conclusion, our results demonstrate that P2X7R plays a significant role in the development of atherosclerosis and regulates NLRP3 inflammasome activation by promoting PKR phosphorylation.
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Kuang
authors.initials: K
authors.lastname: Peng
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Lushan
authors.initials: L
authors.lastname: Liu
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Dangheng
authors.initials: D
authors.lastname: Wei
authors.affiliation: Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Yuncheng
authors.initials: Y
authors.lastname: Lv
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Medical College, University of South China, Hengyang, Hunan 421001, P.R. China.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Xiong
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Afrasyab
authors.initials: A
authors.lastname: Altaf
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Dan
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Qu
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003331:Coronary Vessels / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D058486:Receptors, Purinergic P2X7 / Q000235:genetics* / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008077:Lipoproteins, LDL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D058486:Receptors, Purinergic P2X7; C099252:oxidized low density lipoprotein