心肌肥厚的早期分子机制-英文课件.ppt

How Is LCC-RyR Intermolecular Failure Linked to the Global Performance of E-C Coupling * * Early Molecular Mechanism Underlying Cardiac Hypertrophy Youyi Zhang Institute of Vascular Medicine Peking University Third Hospital 12 nm 电压依赖L型钙通道 Ca2+ Ca2+ LCC RyR SR 钙池 Pathological factors Hormones Neurotransmitters Cytokines Force Function maintenance Heart failure Ca2＋ Ca2＋ Early molecular mechanism underlying cardiac hypertrophy ? 1. Ca2+ transients triggered by comparable LCC currents are decreased in amplitude and slowed in heart failure 2. Compensated hypertrophy shows that the cellular aspects of E-C coupling appear to be normal The molecular details underlying defective E-C coupling remain unknown Whether and when the intermolecular process of CICR is modified AAS Pressure-Overload Hypertrophy Model Induced by Aortic Stenosis Hypertrophy 4~7 weeks 50 ?m -70 mV 0 mV, 300 ms 200 ms 1 cm PWD Control DHT * * * * * CHT * Characterize the Cellular E-C Coupling ** ** ** ** RP+70mv RP RP+70mv 100 ms RP LCC-RyR Coupling During Hypertrophy Percentage of Ca2+ sparks triggered by the first Ca2t sparklets Percentage of depolarization pulses that occurred without triggering any Ca2+ sparks 50 ms Coupling latency Control CHT DHT * ** Kinetics of LCC-RyR Coupling ** Time constant for LCC-RyR coupling ? Ca2+ spikes tended to be desynchronized g i h d e f a b c -70 mV 0 mV 10 ?m Control CHT DHT A 50 ms 2 0 ?F/F0 B Dspike a d g b e h c f i ** ** Control CHT DHT Time delay from depolarization to the peak of each Ca2+ spike ** Cellular Tolerance Against Intermolecular Failure Numerical Simulation of Stability Margin stability margin stability margin extended N C D F Seeking Potential Mechanisms Underlying the Intermolecular Failure ? SR Ca2+ Load in Resting Cells A LCC RyR Overlay Con CHT DHT B LCC-RyR Overlapping 0 20 40 60 80 100 (%) Control CHT DHT Structural Arrangement between SR and Cell/T-tubule 0 0.02