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汉族家庭高血压线粒体基因突变

MaternallyInheritedEssentialHypertensionIsAssociatedWiththeNovel4263A>GMutationintheMitochondrial

tRNAIleGeneinaLargeHanChineseFamily

ShiwenWang,*RonghuaLi,AndreaFettermann,ZongbinLi,YapingQian,YuqiLiu,XinjianWang,

AnnaZhou,JunQinMo,LiYang,PingpingJiang,AndreasTaschner,

WalterRossmanith,Min-XinGuan*

Despitematernaltransmissionofhypertensioninsomepedigrees,pathophysiologyofmaternally

inheritedhypertensionremainspoorlyunderstood.

Toestablishacausativelinkbetweenmitochondrialdysfunctionandessentialhypertension.

Atotalof106subjectsfromalargeChinesefamilyunderwentclinical,genetic,molecular,andbiochemicalevaluations.Fifteenof24adultmatrilinealrelativesexhibitedawiderangeofseverityinessentialhypertension,whereasnoneoftheoffspringofaffectedfathershadhypertension.Theageatonsetofhypertensioninthematernalkindredvariedfrom20yearsto69years,withanaverageof44years.Mutationalanalysisoftheirmitochondrialgenomesidentifiedanovelhomoplasmic4263A>GmutationlocatedattheprocessingsiteforthetRNAIle5 -endprecursor.Aninvitroprocessinganalysisshowedthatthe4263A>GmutationreducedtheefficiencyofthetRNAIleprecursor5 -endcleavagecatalyzedbyRNaseP.tRNANorthernanalysisrevealedthatthe4263A>Gmutationcaused 46%reductioninthesteady-stateleveloftRNAIle.Aninvivoprotein-labelinganalysisshowed 32%reductionintherateofmitochondrialtranslationincellscarryingthe4263A>Gmutation.Impairedmitochondrialtranslationisapparentlyaprimarycontributortothereductionsintherateofoverallrespiratorycapacity,malate/glutamate-promotedrespiration,succinate/glycerol-3-phosphate-promotedrespiration,orN,N,N ,N -tetramethyl-p-phenylenediamine/ascorbate–promotedrespira-tionandtheincreasinglevelofreactiveoxygenspeciesincellscarryingthe4263A>Gmutation.

ThesedataprovidedirectevidencethatmitochondrialdysfunctioncausedbymitochondrialtRNAIle

4263A>Gmutationisinvolvedinessentialhypertension.Ourfindingsmayprovidenewinsightsintopathophysiologyofmaternallytransmittedhypertension.(CircRes.2011;108:862-870.)

KeyWords:geneticsⅢhypertensionⅢmitochondriaⅢtranscriptionⅢprocessing

ypertensionisamajorpublichealthproblem,affectingapproximately1billionworldwide.1Theetiologyofhypertensionisnotwellunderstoodbecauseitisoftenamultifactorialcondition.Hypertensioncanbecausedbysingle-geneormultifactorialconditions,resultingfrominter-actionsbetweentheenvironmentandinheritedriskfactors.2Infact,humanhypertensionisaconditionassociatedwithendothelialdysfunctionandoxidativestress.3,4Mitochondrialdysfunctionhasbeenpotentiallyimplicatedinbothhumanandexperimentalhypertension.5–7Specifically,abnormalmi-tochondrialrespirationresultsinoxidativestress,uncoupling

H

oftheoxidativepathwaysforATPsynthesis,andsubsequentfailureofcellularenergeticprocesses.8Aninefficientmetab-olismcausedbymitochondrialdysfunctionsinskeletalandvascularsmoothmusclesmayleadtotheelevationofsystolicbloodpressureandthereforemaybeinvolvedinthedevel-opmentofhypertension.6,7,9,10Inparticular,maternaltrans-missionofhypertensionhasbeenimplicatedinsomepedi-grees,suggestingthatthemutation(s)inmitochondrial(mt)DNAisoneofthemolecularbasesforthisdisorder.10–16However,molecularpathogenesisofmaternallyinheritedhypertensionremainspoorlyunderstood.

OriginalreceivedSeptember2,2010;revisionreceivedJanuary31,2011;acceptedFebruary1,2011.InDecember2010,theaveragetimefromsubmissiontofirstdecisionforalloriginalresearchpaperssubmittedtoCirculationResearchwas14.5days.

FromtheInstituteofGeriatricCardiology(S.W.,Z.L.,Y.L.),ChinesePLAGeneralHospital,Beijing,China;DivisionsofHumanGenetics(R.L.,Y.Q.,X.W.,A.Z.,L.Y.,M.-X.G.)andPathology(J.Q.M.),CincinnatiChildren’sHospitalMedicalCenter,OH;InstituteofGenetics(P.J.,M.-X.G.),CollegeofLifeSciences,ZhejiangUniversity,Hangzhou,Zhejiang,China;CenterforAnatomyandCellBiology(A.F.,A.T.,W.R.),MedicalUniversityofVienna,Austria;andDepartmentofPediatrics(J.Q.M.,M.-X.G.),UniversityofCincinnatiCollegeofMedicine,OH.Bothauthorscontributedequallytothiswork.

CorrespondencetoMin-XinGuan,PhD,InstituteofGenetics,ZhejiangUniversity,Hangzhou,Zhejiang310058,China;E-mailgminxin88@http://www.wenkuxiazai.comormin-xin.guan@http://www.wenkuxiazai.comortoShiwenWang,MD,InstituteofGeriatricCardiology,ChinesePLAGeneralHospital,Beijing,China;E-mailwangshiwen4290@http://www.wenkuxiazai.com.

©2011AmericanHeartAssociation,Inc.CirculationResearchisavailableathttp://www.wenkuxiazai.com

DOI:10.1161/CIRCRESAHA.110.231811

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