CaMKIIδB Mediates Aberrant NCX1 Expression and the Imbalance of NCX1SERCA in Transverse Aortic Constriction-Induced Failing Heart 英文参考文献.docVIP

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CaMKIIδB Mediates Aberrant NCX1 Expression and the Imbalance of NCX1SERCA in Transverse Aortic Constriction-Induced Failing Heart 英文参考文献.doc

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CaMKIIδB Mediates Aberrant NCX1 Expression and the Imbalance of NCX1SERCA in Transverse Aortic Constriction-Induced Failing Heart 英文参考文献

CaMKIIdBMediatesAberrantNCX1Expressionandthe ImbalanceofNCX1/SERCAinTransverseAortic Constriction-InducedFailingHeart Ying-MeiLu2,3,JiyunHuang1,NorifumiShioda3,KohjiFukunaga3,YasufumiShirasaki4,Xiao-mingLi2, FengHan1* 1InstituteofPharmacology,ToxicologyandBiochemicalPharmaceutics,ZhejiangUniversity,Hangzhou,China,2DepartmentofNeurobiology,ZhejiangUniversitySchool of Medicine, Hangzhou, China, 3Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan, 4Biological Research Laboratories,Daiichi-SankyoPharmaceuticalCo.,Ltd.Tokyo,Japan Abstract Ca2+/calmodulin-dependentproteinkinaseIIdB(CaMKIIdB)isoneofthepredominantisoformsofCaMKIIintheheart.The preciseroleofCaMKIIdBinthetranscriptionalcross-talkofCa -handlingproteinsduringheartfailureremainsunclear.In 2+ + 2+ this work, we aim to determine the mechanism of CaMKIIdB in modulating the expression of sarcolemmal Na –Ca exchange(NCX1).WealsoaimtoaddressthepotentialeffectsofcalmodulinantagonismontheimbalanceofNCX1and sarcoendoplasmicreticulumCa ATPase(SERCA)duringheartfailure.Eightweeksaftertransverseaorticconstriction(TAC)- 2+ inducedheartfailureinmice,wefoundthattheheartweight/tibialength(HW/TL)ratioandthelungweight/bodyweight (LW/BW) ratio increased by 59% and 133%, respectively. We further found that the left ventricle-shortening fraction decreased by 40% compared with the sham-operated controls. Immunoblotting revealed that the phosphorylation of CaMKIIdBsignificantlyincreased8weeksafterTAC-inducedheartfailure.NCX1proteinlevelswerealsoelevated,whereas SERCA2 protein levels decreased in the same animal model. Moreover, transfection of active CaMKIIdB significantly increasedNCX1proteinlevelsinadultmousecardiomyocytesviaclassIIahistonedeacetylase(HDAC)/myocyteenhancer factor-2 (MEF2)-dependent signaling. In addition, pharmacological inhibition of calmodulin/CaMKIIdB activity improved cardiac function in TAC mice, which partially normalized the imbalance between NCX1 a