Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells 英文参考文献.docVIP

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Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells 英文参考文献.doc

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Downregulation of ETS Rescues Diabetes-Induced Reduction of Endothelial Progenitor Cells 英文参考文献

DownregulationofETSRescuesDiabetes-Induced ReductionofEndothelialProgenitorCells FlorianHartmutSeeger1,LinpingChen1,IoakimSpyridopoulos1,JoachimAltschmied2 ,Alexandra Aicher1,JudithHaendeler1,2¤* 1Molecular Cardiology, Department of Internal Medicine III, University of Frankfurt, Frankfurt, Germany, 2Cell Biology Molecular Aging Research, IUF (Institut fu¨r UmweltmedizinischeForschung)attheUniversityofDuesseldorfgGmbH,Duesseldorf,Germany Abstract Background:Transplantationofvasculogenicprogenitorcells(VPC)improvesneovascularizationafterischemia.However, patients with type 2 diabetes mellitus show a reduced VPC number and impaired functional activity. Previously, we demonstratedthatp38kinaseinhibitionpreventsthenegativeeffectsofglucoseonVPCnumberbyincreasingproliferation anddifferentiationtowardstheendotheliallineageinvitro.Moreover,thefunctionalcapacityofprogenitorcellsisreduced inamousemodelofmetabolicsyndromeincludingtype2diabetes(Leprdb)invivo. Findings:Theaimofthisstudywastoelucidatetheunderlyingsignallingmechanismsinvitroandinvivo.Therefore,we performedDNA-proteinbindingarraysinthebonemarrowofmicewithmetabolicsyndrome,inblood-derivedprogenitor cellsofdiabeticpatientsaswellasinVPCexvivotreatedwithhighlevelsofglucose.ThetranscriptionalactivationofETS transcription factors was increased in all samples analyzed. Downregulation of ETS1 expression by siRNA abrogated the reductionofVPCnumberinducedbyhigh-glucosetreatment.Inaddition,weobservedaconcomitantsuppressionofthe non-endothelialETS-targetgenesmatrixmetalloproteinase9(MMP9)andCD115uponshorttermlentiviraldeliveryofETS- specific shRNAs. Long term inhibition of ETS expression by lentiviral infection increased the number of cells with the endothelialmarkersCD144andCD105. Conclusion: These data demonstrate that diabetes leads to dysregulated activation of ETS, which blocks the functional activityofprogenitorcellsandtheircommitmenttowardstheendothelialcelllineage. Citation:SeegerFH,ChenL,SpyridopoulosI,AltschmiedJ,