Phosphodiesterase 2A is a major negative regulator of iNOS expression in lipopolysaccharide‐treated mouse alveolar macrophages

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: cyclic nucleotide;    pneumonia;    acute lung injury;    nitric oxide;    atrial natriuretic peptide;   

DOI  :  10.1189/jlb.3A0314-152R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

PDE2Aisadual‐functionPDEthatisstimulatedbycGMPtohydrolyzecAMPpreferentially.Inatwo‐hitmodelofALI,wefoundpreviouslythatPDE2AdecreasedlungcAMP,up‐regulatedlungiNOS,andexacerbatedALI.RecentdatasuggestthatmacrophageiNOSexpressioncontributestoALIbutlater,promoteslung‐injuryresolution.However,macrophageiNOSisincreasedbycAMP,suggestingthatPDE2AcouldnegativelyregulatemacrophageiNOSexpression.Totestthis,weexaminedtheeffectsofmanipulatingPDE2AexpressionandfunctiononLPS‐inducediNOSexpressioninamouseAMcellline(MH‐S)andprimarymouseAMs.InMH‐Scells,LPS(100ng/ml)increasedPDE2Aexpressionby15%at15minand50%at6hbeforedecreasingat24hand48h.iNOSexpressionappearedat6handremainedincreased48hpost‐LPS.ComparedwithcontrolAd,Ad.PDE2A‐shRNAenhancedLPS‐inducediNOSexpressionfurtherbyfourfold,aneffectmimickedbythePDE2AinhibitorBAY60–7550.AdenoviralPDE2AoverexpressionortreatmentwithANPdecreasedLPS‐inducediNOSexpression.ANP‐inducedinhibitionofiNOSwaslostbyknockingdownPDE2Aandwasnotmimickedby8‐pCPT‐cGMP,acGMPanalogthatdoesnotstimulatePDE2Aactivity.Finally,wefoundthatinprimaryAMsfromLPS‐treatedmice,PDE2AknockdownalsoincreasediNOSexpression,consistentwiththeMH‐Scelldata.WeconcludethatincreasedAMPDE2AisanimportantnegativeregulatorofmacrophageiNOSexpression...

【 授权许可】

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