CaMKII和心力衰竭(英文)-课件.pptVIP

INTRODUCTION 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. Summary CaMKII 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. What is the long term effect of CaMKII inhibition on cardiac function ? Summary Increased 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 and Heart Failure Yanggan Wang, MD, PhD 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 Gαq TRPC TRPC SAC Ca2+ (fosfatasi) CaMK:Protein chinasi Ca/Calmodulina-dipendente MEF:myocyte enhancer factor Nuclear Factor of Activated T cells Histone Deacetylase Ca2+ Ca2+/CaM Inactive 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 hypertrophy 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): 1230–1