Effects of ADMA upon Gene Expression An Insight into the Pathophysiological Significance of Raised Plasma ADMA 英文参考文献.docVIP

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Effects of ADMA upon Gene Expression An Insight into the Pathophysiological Significance of Raised Plasma ADMA 英文参考文献.doc

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Effects of ADMA upon Gene Expression An Insight into the Pathophysiological Significance of Raised Plasma ADMA 英文参考文献

o Openaccess,freelyavailableonline PL S MEDICINE EffectsofADMAuponGeneExpression: AnInsightintothePathophysiological SignificanceofRaisedPlasmaADMA Caroline L.Smith*,Shelagh Anthony, Mike Hubank, James M.Leiper, Patrick Vallance CentreforClinicalPharmacologyandTherapeutics,DivisionofMedicine,UniversityCollegeLondon,London,UnitedKingdom CompetingInterests:University CollegeLondonholdspatentson DDAHasadrugtarget(notrelevant tothepresentstudy). ABSTRACT Background Asymmetric dimethylarginine (ADMA) is a naturally occurring inhibitor of nitric oxide synthesisthataccumulatesinawiderangeofdiseasesassociatedwithendothelialdysfunction and enhanced atherosclerosis. Clinical studies implicate plasma ADMA as a major novel cardiovascularriskfactor,butthemechanismsbywhichlowconcentrationsofADMAproduce adverseeffectsonthecardiovascularsystemareunclear. AuthorContributions:CLS,JML, andPVdesignedthestudy.CLS,SA, MH,JML,andPVanalyzedthedata. CLS,MH,JML,andPVcontributedto writingthepaper. AcademicEditor:IvorBenjamin, UniversityofUtah,UnitedStatesof America MethodsandFindings Citation:SmithCL,AnthonyS, HubankM,LeiperJM,VallanceP (2005)EffectsofADMAupongene expression:Aninsightintothe pathophysiologicalsignificanceof raisedplasmaADMA.PLoSMed 2(10):e264. Wetreatedhumancoronaryarteryendothelialcellswithpathophysiologicalconcentrations of ADMA and assessed the effects on gene expression using U133A GeneChips (Affymetrix). Changesinseveralgenes,includingbonemorphogeneticprotein2induciblekinase(BMP2K), SMA-relatedprotein5(Smad5),bonemorphogeneticproteinreceptor1A,andproteinarginine methyltransferase 3 (PRMT3; also known as HRMT1L3), were confirmed by Northern blotting, quantitativePCR,andinsomeinstancesWesternblottinganalysistodetectchangesinprotein expression. To determine whether these changes also occurred in vivo, tissue from gene deletionmicewithraisedADMAlevelswasexamined.Morethan50genesweresignificantly alteredinendothelialcellsaftertreatmentwithpathophysiologicalconcentrations