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PTH诱导心肌细胞肥大的机制及立普妥的干预作用.docx

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PTH诱导心肌细胞肥大的机制及立普妥的干预作用 Introduction Parathyroidhormone(PTH)isaproteinhormoneproducedbytheparathyroidglands.PTHplaysacriticalroleinregulatingcalciumandphosphatehomeostasis.Itactsonthebones,kidneysandintestinestoincreasecalciumandphosphatelevelsintheblood.Inaddition,studieshaveshownthatPTHisinvolvedintheregulationofcardiacfunction.PTHhasbeenshowntoinducecardiachypertrophybyactivatinganumberofsignalingpathways.ThisarticlewilldiscussthemechanismsbywhichPTHinducescardiomyocytehypertrophyandtheroleofthedrug,L-163,191,ininterveningintheseprocesses. PTHInducesCardiomyocyteHypertrophy Cardiachypertrophyischaracterizedbyanincreaseinthesizeofindividualcardiomyocytesandtheoverallweightoftheheart.Atthemolecularlevel,hypertrophicgrowthisinducedbyalterationsinanumberofsignalingpathwaysregulatedbyavarietyofgrowthfactors,hormonesandextracellularmatrixproteins.SeveralstudieshavereportedthatPTHcaninducecardiachypertrophyinbothinvitroandinvivomodels. ThemechanismbywhichPTHinducescardiomyocytehypertrophyhasbeenextensivelystudied.OneoftheprimarypathwaysthatPTHinteractswithisthecAMPdependentproteinkinase(PKA)pathway.PTHincreasesthelevelsofintracellularcAMP,whichbindstoandactivatesPKA.ActivePKAthenphosphorylatescertaintranscriptionfactors,includingcAMPresponseelement-bindingprotein(CREB),whichregulatestheexpressionofvariousgenesrelatedtocardiomyocytehypertrophy.Inaddition,PTHalsoactivatesthemitogen-activatedproteinkinases(MAPKs)includingERK,JNKandp38,whichpromoteCREBphosphorylationandgeneexpression. AnothercriticalpathwaywhichPTHcanactivateisthecalcineurin/NFATpathway.PTHhasbeenshowntoactivatecalcineurin,whichdephosphorylatesNFAT,allowingittotranslocatetothenucleuswhereitcanactivateaseriesofhypertrophy-relatedgenes.Moreover,PTHcanincreasetheexpressionofanumberofotherhypertrophy-relatedproteins,includingamyosinheavychain,ANF,andβ-MHC,amongothers.Insummary,PTHcanexertitshypertrophiceffectsoncardiomyocytesthroughseveralsignalingpathways,whichinteractandregulatetheexpressionofgenesinvolvedinc