CaMKII和心力衰竭英文.pptxVIP

CaMKII和心力衰竭英文第1页/共21页 Natriuretic peptideReceptorsNeural hormonal signalsBiomechanical stressPKCPKAGuanylyl Cyclase Adenylyl cyclaseStretch sensorMAPK CalcineurinCaMKIITranscription factorsNFAT, MEF2, GATA4 Fetal gene activation and cardiac remodelingGαqTRPCTRPCSACCa2+ 第2页/共21页 (fosfatasi)CaMK:Protein chinasi Ca/Calmodulina-dipendenteMEF:myocyte enhancer factorNuclear 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-overexpression 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 KO normalizes the expression of Ca2+ regulatory proteins and reduces RyR2 phosphorylation and Ca2+ leak after TABJ Clin Invest. 2009, 119(5): 1230–1240 第9页/共21页 J Clin Invest. 2009, 119(5): 1230–1240 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 potential 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 CaMKIIδ KO mice第13页/共21页 WTCaMKII KOWT HFCaMKII KO HF第14页/共21页 Unchanged CaMKIIg expression and reduced CaMKII activity in CaMKIId KO HFWT HFCaMKIIdKO HFp-PLB (Thr17)a-ActininCaMKIIgd54 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-adrenergic stimulation第17页/共21页 P0.05P0.05CaMKII inhibition in HF reduces cardiac reserve to b-adrenergic stimulation第18页/共21页 Summar