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1、CaMKII and Heart FailureYanggan Wang, MD, PhD CaMKII和心力衰竭(英文)幻灯n n5 million patients with Heart failure in 5 million patients with Heart failure in US. US. 0.5 million new HF patients and 0.25 0.5 million new HF patients and 0.25 million deaths annually.million deaths annually.n nThe precise mechani
2、sms underlying The precise mechanisms underlying the contractile and electrical the contractile and electrical abnormalities of hypertrophy and HF abnormalities of hypertrophy and HF remains elusive.remains elusive.n nIneffective therapies.Ineffective therapies. INTRODUCTIONCaMKIICaMKII和心力衰竭和心力衰竭( (
3、英文英文) )幻灯幻灯Natriuretic peptideReceptorsNeural hormonal signalsBiomechanical stressPKCPKAGuanylyl Cyclase Adenylyl cyclaseStretch sensorMAPK CalcineurinCaMKIITranscription factorsNFAT, MEF2, GATA4 Fetal gene activation and cardiac remodelingGqTRPCTRPCSACCa2+ CaMKII和心力衰竭(英文)幻灯 (fosfatasi)CaMK:Protein
4、chinasi Ca/Calmodulina-dipendenteMEF:myocyte enhancer factorNuclear Factor of Activated T cellsHistone DeacetylaseCa2+CaMKII和心力衰竭(英文)幻灯Ca2+/CaMInactivePhosphateactiveCa2+-independentactiveCaM-bandactiveCaM-trappedPhosphataseCardiac CaMKII activationCaMKII和心力衰竭(英文)幻灯Role of Cardiac CaMKIICaMKII和心力衰竭(
5、英文)幻灯Circulation Research. 2004;94:e61. CaMKII and E-C CouplingCaMKII和心力衰竭(英文)幻灯CaMKII-overexpression causes dysfunction of E-C coupling and HFCaMKII和心力衰竭(英文)幻灯Mechanisms for CaMKII-induced cardiac hypertrophy and failureCaMKII和心力衰竭(英文)幻灯CaMKIId d KO normalizes the expression of Ca2+ regulatory prot
6、eins and reduces RyR2 phosphorylation and Ca2+ leak after TABJ Clin Invest. 2009, 119(5): 12301240 CaMKII和心力衰竭(英文)幻灯J Clin Invest. 2009, 119(5): 12301240 CaMKII inhibition protects against structural heart diseaseCaMKII和心力衰竭(英文)幻灯SummaryCaMKII plays an important role in the development of cardiac hy
7、pertrophy and failure by activation of hypertrophic gene grogram and increasing SR Ca2+ leak and myocyte apoptosis.CaMKII-inhibition is a potential clinical therapeutic target.CaMKII和心力衰竭(英文)幻灯What is the long term effect of CaMKII inhibition on cardiac function ?CaMKII和心力衰竭(英文)幻灯A pressure-overload
8、 HF model has been generated by severe thoracic aortic banding (sTAB) in CaMKII KO miceCaMKII和心力衰竭(英文)幻灯WTCaMKII KOWT HFCaMKII KO HFCaMKII和心力衰竭(英文)幻灯Unchanged CaMKIIg g expression and reduced CaMKII activity in CaMKIId d KO HFWT HFCaMKIId dKO HFp-PLB (Thr17)a a-ActininCaMKIIg gd d54 KD7 KD42 KD62 KD
9、 CaMKII和心力衰竭(英文)幻灯CaMKII inhibition in HF reduces SR Ca2+ leak but slows Ca2+ transient decay and relaxationCaMKII和心力衰竭(英文)幻灯CaMKII inhibition in HF reduces cardiac reserve to b b-adrenergic stimulationCaMKII和心力衰竭(英文)幻灯P0.05P0.05CaMKII inhibition in HF reduces cardiac reserve to b b-adrenergic stimu
10、lationCaMKII和心力衰竭(英文)幻灯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.CaMKII和心力衰竭(英文)幻灯CaMKII和心力衰竭(英文)幻灯
