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1、5 million patients with Heart failure in US.0.5 million new HF patients and 0.25 million deaths annually.The precise mechanisms underlying the contractile and electrical abnormalities of hypertrophy and HF remains elusive.Ineffective therapies.INTRODUCTION第1页/共21页Natriuretic peptideReceptorsNeural h
2、ormonal signalsBiomechanical stressPKCPKAGuanylyl Cyclase Adenylyl cyclaseStretch sensorMAPK CalcineurinCaMKIITranscription factorsNFAT,MEF2,GATA4 Fetal gene activation and cardiac remodelingGqTRPCTRPCSACCa2+第2页/共21页(fosfatasi)CaMK:Protein chinasi Ca/Calmodulina-dipendenteMEF:myocyte enhancer factor
3、Nuclear Factor of Activated T cellsHistone DeacetylaseCa2+第3页/共21页Ca2+/CaMInactivePhosphateactiveCa2+-independentactiveCaM-bandactiveCaM-trappedPhosphataseCardiac CaMKII activation第4页/共21页Role of Cardiac CaMKII第5页/共21页Circulation Research.2004;94:e61.CaMKII and E-C Coupling第6页/共21页CaMKII-overexpress
4、ion causes dysfunction of E-C coupling and HF第7页/共21页Mechanisms for CaMKII-induced cardiac hypertrophy and failure第8页/共21页CaMKIId d KO normalizes the expression of Ca2+regulatory proteins and reduces RyR2 phosphorylation and Ca2+leak after TABJ Clin Invest.2009,119(5):12301240 第9页/共21页J Clin Invest.
5、2009,119(5):12301240 CaMKII inhibition protects against structural heart disease第10页/共21页SummaryCaMKII plays an important role in the development of cardiac hypertrophy and failure by activation of hypertrophic gene grogram and increasing SR Ca2+leak and myocyte apoptosis.CaMKII-inhibition is a pote
6、ntial clinical therapeutic target.第11页/共21页What is the long term effect of CaMKII inhibition on cardiac function?第12页/共21页A pressure-overload HF model has been generated by severe thoracic aortic banding(sTAB)in CaMKII KO mice第13页/共21页WTCaMKII KOWT HFCaMKII KO HF第14页/共21页Unchanged CaMKIIg g expressi
7、on and reduced CaMKII activity in CaMKIId d KO HFWT HFCaMKIId dKO HFp-PLB(Thr17)a a-ActininCaMKIIg gd d54 KD7 KD42 KD62 KD 第15页/共21页CaMKII inhibition in HF reduces SR Ca2+leak but slows Ca2+transient decay and relaxation第16页/共21页CaMKII inhibition in HF reduces cardiac reserve to b b-adrenergic stimu
8、lation第17页/共21页P0.05P0.05CaMKII inhibition in HF reduces cardiac reserve to b b-adrenergic stimulation第18页/共21页SummaryIncreased CaMKII activity contributes to the dysfunction of cardiac E-C coupling in HF.However,long term inhibition of CaMKII in HF may reduce cardiac reserve to b-adrenergic activation,suggesting that the physiologic CaMKII activity plays an important role in maintaining heart function(contraction and relaxation)in HF under the condition of increased workload or stress.CaMKII-inhibition in HF must be considered with caution.第19页/共21页第20页/共21页感谢您的观看！第21页/共21页