SERPINA3K Prevents Oxidative Stress Induced Necrotic Cell Death by Inhibiting Calcium Overload 英文参考文献.docVIP

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SERPINA3K Prevents Oxidative Stress Induced Necrotic Cell Death by Inhibiting Calcium Overload 英文参考文献.doc

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SERPINA3K Prevents Oxidative Stress Induced Necrotic Cell Death by Inhibiting Calcium Overload 英文参考文献

SERPINA3KPreventsOxidativeStressInducedNecrotic CellDeathbyInhibitingCalciumOverload BinZhang,Jian-xingMa* DepartmentofCellBiology,DepartmentofMedicine,TheUniversityofOklahomaHealthSciencesCenter,OklahomaCity,Oklahoma,UnitedStatesofAmerica Abstract Background:SERPINA3K,anextracellularserineproteinaseinhibitor(serpin),hasbeenshowntohavedecreasedlevelsin theretinasofdiabeticrats,whichmaycontributetodiabeticretinopathy.ThefunctionofSERPINA3Kintheretinahasnot beeninvestigated. Methodology/PrincipalFindings:ThepresentstudyidentifiedanovelfunctionofSERPINA3K,i.e.itprotectsretinalcells againstoxidativestress-inducedcelldeathincludingretinalneuronalcellsandMu¨llercells.Flow-cytometryshowedthatthe protective effect of SERPINA3K on Mu¨ller cells is via reducing oxidation-induced necrosis. Measurements of intracellular calcium concentration showed that SERPINA3K prevented the intracellular calcium overload induced by H2O2. A similar protectiveeffectwasobservedusingacalciumchelator(BAPTA/AM).Further,SERPINA3Kinhibitedthephosphorylationof phospholipase C (PLC)-gamma1 induced by H2O2. Likewise, a specific PLC inhibitor showed similar protective effects on Mu¨llercellsexposedtoH2O2.Furthermore,theprotectiveeffectofSERPINA3KwasattenuatedbyaspecificPLCactivator (m-3M3FBS).Finally,inabindingassay,SERPINA3KdisplayedsaturableandspecificbindingonMu¨llercells. Conclusion/Significance: These results for the first time demonstrate that SERPINA3K is an endogenous serpin which protects cells from oxidative stress-induced cells death, and its protective effect is via blocking the calcium overload throughthePLCpathway.ThedecreasedretinallevelsofSERPINA3Kmayrepresentanewpathogenicmechanismforthe retinalMu¨llercelldysfunctionandneuronlossindiabetes. Citation: Zhang B, Ma J-x (2008) SERPINA3K Prevents Oxidative Stress Induced Necrotic Cell Death by Inhibiting Calcium Overload. PLoS ONE 3(12): e4077. doi:10.1371/journal.pone.0004077 Editor:MarkR.Cookson,NationalInstitutesofHealth,UnitedStatesofA