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1、,CaMKII and Heart Failure Yanggan Wang, MD, PhD,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.,INTR
2、ODUCTION,Natriuretic peptide,Receptors,Neural hormonal signals,Biomechanical stress,PKC,PKA,Guanylyl Cyclase,Adenylyl cyclase,Stretch sensor,MAPK,Calcineurin,CaMKII,Transcription factors NFAT, MEF2, GATA4,Fetal gene activation and cardiac remodeling,Gq,TRPC,TRPC,SAC,Ca2+,(fosfatasi),Ca2+/CaM,Inactiv
3、e,Phosphate,active Ca2+-independent,active CaM-band,active CaM-trapped,Phosphatase,Cardiac CaMKII activation,Role of Cardiac CaMKII,Circulation Research. 2004;94:e61.,CaMKII and E-C Coupling,CaMKII-overexpression causes dysfunction of E-C coupling and HF,Mechanisms for CaMKII-induced cardiac hypertr
4、ophy and failure,CaMKIId KO normalizes the expression of Ca2+ regulatory proteins and reduces RyR2 phosphorylation and Ca2+ leak after TAB,J Clin Invest. 2009, 119(5): 12301240,J Clin Invest. 2009, 119(5): 12301240,CaMKII inhibition protects against structural heart disease,Summary,CaMKII plays an i
5、mportant 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.,What is the long term effect of CaMKII inhibition on cardiac function ?,A pr
6、essure-overload HF model has been generated by severe thoracic aortic banding (sTAB) in CaMKII KO mice,Unchanged CaMKIIg expression and reduced CaMKII activity in CaMKIId KO HF,WT HF,CaMKIId KO HF,p-PLB (Thr17),a-Actinin,CaMKII,gd,54 KD,7 KD,42 KD,62 KD,CaMKII inhibition in HF reduces SR Ca2+ leak b
7、ut slows Ca2+ transient decay and relaxation,CaMKII inhibition in HF reduces cardiac reserve to b-adrenergic stimulation,CaMKII inhibition in HF reduces cardiac reserve to b-adrenergic stimulation,Summary,Increased CaMKII activity contributes to the dysfunction of cardiac E-C coupling in HF. However
8、, 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.,