Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy 英文参考文献.docVIP

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Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy 英文参考文献.doc

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Primary Role of Functional Ischemia, Quantitative Evidence for the Two-Hit Mechanism, and Phosphodiesterase-5 Inhibitor Therapy in Mouse Muscular Dystrophy 英文参考文献

PrimaryRoleofFunctionalIschemia,Quantitative EvidencefortheTwo-HitMechanism,and Phosphodiesterase-5InhibitorTherapyinMouse MuscularDystrophy AkihiroAsai1,2,NitaSahani1,MasaoKaneki1,YasuyoshiOuchi2,J.A.JeevendraMartyn1,ShingoEgusaYasuhara1* 1DepartmentofAnesthesiologyandCriticalCare,ShrinersHospitalforChildren,MassachusettsGeneralHospital,HarvardMedicalSchool,Boston, Massachusetts,UnitedStatesofAmerica,2DepartmentofGeriatricMedicine,GraduateSchoolofMedicine,TheUniversityofTokyo,Tokyo,Japan Background.DuchenneMuscularDystrophy(DMD)ischaracterizedbyincreasedmuscledamageandanabnormalbloodflow after muscle contraction: the state of functional ischemia. Until now, however, the cause-effect relationship between the pathogenesisofDMDandfunctionalischemiawasunclear.Weexamined(i)whetherfunctionalischemiaisnecessarytocause contraction-induced myofiber damage and (ii) whether functional ischemia alone is sufficient to induce the damage. Methodology/PrincipalFindings.Invivomicroscopywasusedtodocumentassaysdevelopedtomeasureintramuscularred bloodcellflux,toquantifytheamountofvasodilatorymoleculesproducedfrommyofibers,andtodeterminetheextentof myofiberdamage.Reversaloffunctionalischemiaviapharmacologicalmanipulationpreventedcontraction-inducedmyofiber damageinmdxmice,themurineequivalentofDMD.Thisresultindicatesthatfunctionalischemiaisrequiredfor,andthusan essentialcauseof,muscledamageinmdxmice.Next,todeterminewhetherfunctionalischemiaaloneisenoughtoexplainthe disease,theextentofischemiaandtheamountofmyofiberdamagewerecomparedbothincontrolandmdxmice.Incontrol mice,functionalischemiaalonewasfoundinsufficienttocauseasimilardegreeofmyofiberdamageobservedinmdxmice. Additionalmechanismsarelikelycontributingtocausemoreseveremyofiberdamageinmdxmice,suggestiveoftheexistence ofa‘‘two-hit’’mechanisminthepathogenesisofthisdisease.Conclusions/Significance.Evidencewasprovidedsupporting the essential role of functional ischemia in contraction-induced myofiber damage in mdx mice. Furthermore, t