内皮细胞的硝酸氧化物Synthase(eNOS)击倒老鼠有瑕疵线粒体ss氧化作用

EndothelialNitricOxideSynthase(eNOS)KnockoutMiceHaveDefectiveMitochondrialß-OxidationEricLeGouill1,MariaJimenez2,ChristopheBinnert3,Pierre-YvesJayet4,SebastienThalmann4,PascalNicod4,UrsScherrer4,andPeterVollenweider41DepartmentofCellularBiologyandMorphology,UniversityofLausanne,Switzerland2DepartmentofBiochemistryandPhysiology,CMU,UniversityofGeneva,Geneva,Switzerland3InstituteofPhysiology,UniversityofLausanne,Lausanne,Switzerland4DepartmentofInternalMedicineandtheBotnarCenterforClinicalResearch,CentreHospitalierUniversitaireVaudois,Lausanne,SwitzerlandAddresscorrespondenceandreprintrequeststoPeterVollenweider,MD,DepartmentofInternalMedicine,BH10.624,CentreHospitalierUniversitaireVaudois,CH-1011Lausanne,Switzerland.E-mail:[e-mail]:eNOS,endothelialnitricoxidesynthase;FFA,freefattyacid;L-NAME,NG-nitro-L-argininemethylester;LPL,lipoproteinlipase;NOS,nitricoxidesynthase;nNOS,neuronalnitricoxidesynthaseOBJECTIVE—Recentobservationsindicatethatthedeliveryofnitricoxidebyendothelialnitricoxidesynthase(eNOS)isnotonlycriticalformetabolichomeostasis,butcouldalsobeimportantformitochondrialbiogenesis,akeyorganelleforfreefattyacid(FFA)oxidationandenergyproduction.BecausemicedeficientforthegeneofeNOS(eNOS–/–)haveincreasedtriglyceridesandFFAlevels,inadditiontohypertensionandinsulinresistance,wehypothesizedthattheseknockoutmicemayhavedecreasedenergyexpenditureanddefectiveß-oxidation.RESEARCHDESIGNANDMETHODS—SeveralmarkersofmitochondrialactivitywereassessedinC57BL/6Jwild-typeoreNOS–/–miceincludingtheenergyexpenditureandoxygenconsumptionbyindirectcalorimetry,invitroß-oxidationinisolatedmitochondriafromskeletalmuscle,andexpressionofgenesinvolvedinfattyacidoxidation.RESULTS—eNOS–/–micehadmarkedlylowerenergyexpenditure(–10%,P0.05)andoxygenconsumption(–15%,P0.05)thancontrolmice.Thiswasassociatedwitharoughly30%decreaseofthemitochondriacontent(P0.05)and,mostimportantly,withmitochondrialdysfunction,asevidencedbyamarkedlylowerß-oxidationofsubsarcolemmalmitochondriainskeletalmuscle(–30%,P0.05).Finally,impairedmitochondrialß-oxidationwasassociatedwithasignificantincreaseoftheintramyocellularlipidcontent(30%,P0.05)ingastrocnemiusmuscle.CONCLUSIONS—ThesedataindicatethatelevatedFFAandtriglycerideineNOS–/–miceresultindefectivemitochondrialß-oxidationinmusclecells.