Abdominal aortic aneurysm(AAA)is defined as a dilated aorta in diameter at least 1.5 times of a normal aorta.Our previous studies found that activating α7 nicotinic acetylcholine receptor(α7nAChR)had a protective effect on vascular injury.This work was to investigate whether activating α7nAChR could influence AAA formation and explore its mechanisms.AAA models were established by angiotensin Ⅱ(Ang Ⅱ)infusion in ApoE-/-mice or in wild type and α7nAChR-/-mice.In vitro mouse aortic smooth muscle(MOVAS)cells were treated with tumor necrosis factor-α(TNF-α).PNU-282987 was chosen to activate α7nAChR.We found that cell pyroptosis effector GSDMD and NLRP3 inflammasome were activated in abdominal aorta,and inflammatory cytokines in serum were elevated in AAA models of ApoE-/-mice.Activating α7nAChR reduced maximal aortic diameters,preserved elastin integrity and decreased inflammatory responses in ApoE-/-mice with Ang Ⅱ infusion.While α7nAChR-/-mice led to aggravated aortic injury and increased inflammatory cytokines with Ang Ⅱ infusion when compared with wild type.Moreover,activating α7nAChR inhibited NLRP3/caspase-1/GSDMD pathway in AAA model of ApoE-/-mice,while a7nAChR deficiency promoted this pathway.In vitro,N-acetylcysteine(NAC)inhibited NLRP3 inflammasome activation and NLRP3 knockdown reduced GSDMD expression,in MOVAS cells treated with TNF-α.Furthermore,activating α7nAChR inhibited oxidative stress,reduced NLRP3/GSDMD expression,and decreased cell pyroptosis in MOVAS cells with TNF-α.In conclusion,our study found that activating α7nAChR retarded AAA through inhibiting pyroptosis mediated by NLRP3 inflammasome.These suggested that α7nAChR would be a potential pharmacological target for AAA.

Hui Fu;Qi-rui Shen;Yi Zhao;Min Ni;Can-can Zhou;Ji-kuai Chen;Chen Chi;Dong-jie Li;Guang Liang;Fu-ming Shen

Department of Pharmacy,Shanghai Tenth People's Hospital,Tongji University School of Medicine,Shanghai 200072,China;Chemical Biology Research Center,School of Pharmaceutical Sciences,Wenzhou Medical University,Wenzhou 325035,China;Department of Health Toxicology,Faculty of Naval Medicine,Second Military Medical University/Naval Medical University,Shanghai 200433,China;Institute of Nuclear Medicine,Tongji University School of Medicine,Shanghai 200092,China

中国药理学报（英文版）

[1]Hui Fu;Qi-rui Shen;Yi Zhao;Min Ni;Can-can Zhou;Ji-kuai Chen;Chen Chi;Dong-jie Li;Guang Liang;Fu-ming Shen-.Activating α7nAChR ameliorates abdominal aortic aneurysm through inhibiting pyroptosis mediated by NLRP3 inflammasome)[J].中国药理学报（英文版）,2022(10):2585-2595

Activating,ameliorates,abdominal,aortic,aneurysm,through,inhibiting,pyroptosis,mediated,by,NLRP3,inflammasome,Abdominal,AAA,defined,dilated,aorta,least,times,normal,Our,previous,studies,found,that,activating,nicotinic,acetylcholine,receptor,had,protective,vascular,injury,This,work,was,investigate,whether,could,influence,formation,explore,its,mechanisms,models,were,established,angiotensin,Ang,infusion,ApoE,mice,wild,type,In,vitro,mouse,smooth,muscle,MOVAS,cells,treated,tumor,necrosis,PNU,chosen,We,effector,GSDMD,activated,inflammatory,cytokines,serum,elevated,reduced,maximal,diameters,preserved,elastin,integrity,decreased,responses,While,led,aggravated,increased,when,compared,Moreover,inhibited,caspase,pathway,while,a7nAChR,deficiency,promoted,this,acetylcysteine,NAC,activation,knockdown,expression,Furthermore,oxidative,stress,conclusion,our,study,retarded,These,suggested,would,be,potential,pharmacological,target

0.483054