Role of TRPM2 in H2O2-Induced Cell Apoptosis in Endothelial Cells 英文参考文献.docVIP

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Role of TRPM2 in H2O2-Induced Cell Apoptosis in Endothelial Cells 英文参考文献.doc

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Role of TRPM2 in H2O2-Induced Cell Apoptosis in Endothelial Cells 英文参考文献

RoleofTRPM2inH2O2-InducedCellApoptosisin EndothelialCells LeiSun1,Ho-YanYau1,Wei-YanWong1,RonaldALi2,YuHuang1,XiaoqiangYao1* 1LiKaShingInstitute ofHealthSciencesandSchoolofBiomedicalSciences, TheChineseUniversityofHongKong,HongKong,China, 2StemCellandRegenerative MedicineConsortium,TheUniversityofHongKong,HongKong,China Abstract Melastatin-liketransientreceptorpotentialchannel2(TRPM2)isanoxidant-sensitiveandcationicnon-selectivechannelthat isexpressedinmammalianvascularendothelium.HereweinvestigatedthefunctionalroleofTRPM2channelsinhydrogen 2+ 2+ peroxide(H2O2)-inducedcytosolicCa ([Ca ]i)elavation,whole-cellcurrentincrease,andapoptoticcelldeathinmurine heartmicrovesselendothelialcelllineH5V.ATRPM2blockingantibody(TM2E3),whichtargetstheE3regionneartheion 2+ permeation pore of TRPM2, was developed. Treatment of H5V cells with TM2E3 reduced the [Ca ]i rise and whole-cell currentchangeinresponsetoH2O2.SuppressingTRPM2expressionusingTRPM2-specificshorthairpinRNA(shRNA)had similar inhibitory effect. H2O2-induced apoptotic cell death in H5V cells was examined using MTT assay, DNA ladder formation analysis, and DAPI-based nuclear DNA condensation assay. Based on these assays, TM2E3 and TRPM2-specific shRNAboth showedprotectiveeffect againstH2O2-inducedapoptotic celldeath. TM2E3 andTRPM2-specific shRNAalso protectthecellsfromtumornecrosisfactor(TNF)-a-inducedcelldeathinMTTassay.Incontrast,overexpressionofTRPM2in 2+ H5V cells resulted in an increased response in [Ca ]i and whole-cell currents to H2O2. TRPM2 overexpression also aggravated the H2O2-induced apoptotic cell death. Downstream pathways following TRPM2 activation was examined. Resultsshowedthat TRPM2activity stimulatedcaspase-8, caspase-9andcaspase-3. Thesefindings stronglysuggest that 2+ TRPM2channelmediatescellularCa overloadinresponsetoH2O2andcontributetooxidant-inducedapoptoticcelldeath invascularendothelialcells.Down-regulatingendogenousTRPM2couldbeameanstoprotectthevascularendothelialcells