Prolyl‐4‐hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions

[摘要] Onamolecularlevel,cellssensechangesinoxygenavailabilitythroughthePHDs,whichregulatetheproteinstabilityoftheα‐subunitofthetranscriptionfactorHIF.Especially,PHD3hasbeenadditionallyassociatedwithapoptoticcelldeath.WehypothesizedthatPHD3playsaroleincell‐fatedecisionsinmacrophages.Therefore,myeloid‐specificPHD3−/−micewerecreatedandanalyzed.PHD3−/−BMDMshowednoalteredHIF‐1αorHIF‐2αstabilizationorincreasedHIFtargetgeneexpressioninnormoxiaorhypoxia.MacrophageM1andM2polarizationwasunchangedlikewise.ComparedwithmacrophagesfromWTlittermates,PHD3−/−BMDMexhibitedasignificantreductioninTUNEL‐positivecellsafterserumwithdrawalortreatmentwithstauroandSNAP.Underthesameconditions,PHD3−/−BMDMalsoshowedlessAnnexinVstaining,whichisrepresentativeformembranedisruption,andindicatedareducedearlyapoptosis.Inanunbiasedtranscriptomescreen,wefoundthatAngptl2expressionwasreducedinPHD3−/−BMDMunderstressconditions.AdditionofrAngptl2rescuedtheantiapoptoticphenotype,demonstratingthatitisinvolvedinthePHD3‐mediatedresponsetowardapoptoticstimuliinmacrophages...

[学科分类] 生理学

[关键词] hypoxia;oxygen sensing;angiopoietin‐like protein;HIF