WWP2 is a HECT-type E3 ubiquitin ligase that regulates various physiological and pathological activities by binding to different substrates,but its role in atherosclerosis(AS)remains largely unknown.The objective of the present study is to investigate the role and underlying molecular mechanisms of WWP2 in endothelial injury.We found that WWP2 expression is significantly decreased in Apolipoprotein E(ApoE)-/-mice.Overexpression of WWP2 attenu-ates oxidative stress and inflammation in AS mice,while knockdown of WWP2 has opposite effects.WWP2 over-expression alleviates oxidized low-density lipoprotein(ox-LDL)-induced human umbilical vein endothelial cell(HUVEC)injury,evidenced by the decreased oxidative stress levels and the secretion of inflammatory cytokines.Programmed cell death 4(PDCD4)is identified as a potential substrate of WWP2.Co-immunoprecipitation(Co-IP)further demonstrates that WWP2 interacts with PDCD4,which is enhanced by ox-LDL treatment.Furthermore,the level of PDCD4 ubiquitination is significantly increased by WWP2 overexpression under the condition of MG132 treatment,while WWP2 knockdown shows opposite results.Subsequently,rescue experiments demonstrate that WWP2 knockdown further aggravates oxidative stress and inflammation in ox-LDL-treated HUVECs,while knock-down of PDCD4 alleviates this effect.Moreover,the use of sn-protoporphyrin(SnPP),an inhibitor of HO-1 pathway,confirms that PDCD4 enhances endothelial injury induced by ox-LDL through inhibiting HO-1 pathway.In conclu-sion,our results suggest that WWP2 protects against atherosclerosis progression via the PDCD4/HO-1 pathway,which may provide a novel treatment strategy for atherosclerosis.

Xingye Wang;Lu Ma;Songlin Zhang;Qiang Song;Xumei He;Jun Wang

Department of Structural Cardiology,the First Affiliated Hospital of Xi'an Jiaotong University,Xi'an 710061,China;Department of Graduate School,Xi'an Shiyou University,Xi'an 710065,China

生物化学与生物物理学报（英文版）

[1]Xingye Wang;Lu Ma;Songlin Zhang;Qiang Song;Xumei He;Jun Wang-.WWP2 ameliorates oxidative stress and inflammation in atherosclerotic mice through regulation of PDCD4/HO-1 pathway)[J].生物化学与生物物理学报（英文版）,2022(08):1057-1067

WWP2,ameliorates,oxidative,stress,inflammation,atherosclerotic,mice,through,regulation,PDCD4,HO,pathway,HECT,type,E3,ligase,that,regulates,various,physiological,pathological,activities,by,binding,different,substrates,but,its,role,atherosclerosis,AS,remains,largely,unknown,objective,present,study,investigate,underlying,molecular,mechanisms,endothelial,injury,We,found,significantly,decreased,Apolipoprotein,ApoE,Overexpression,attenu,while,knockdown,has,opposite,effects,alleviates,oxidized,low,density,LDL,induced,human,umbilical,vein,cell,evidenced,levels,secretion,inflammatory,cytokines,Programmed,death,identified,potential,Co,immunoprecipitation,further,demonstrates,interacts,which,enhanced,treatment,Furthermore,ubiquitination,increased,overexpression,condition,MG132,shows,results,Subsequently,rescue,experiments,aggravates,treated,HUVECs,this,Moreover,use,sn,protoporphyrin,SnPP,inhibitor,confirms,enhances,inhibiting,In,conclu,our,suggest,protects,against,progression,may,provide,novel,strategy

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