心肌肥厚的早期分子机制英文.pptxVIP

心肌肥厚的早期分子机制英文第1页/共22页 12 nm电压依赖L型钙通道Ca2+Ca2+LCCRyR SR钙池第2页/共22页 Pathological factorsHormonesNeurotransmittersCytokinesForceFunction maintenanceHeart failureCa2＋第3页/共22页 Ca2＋Early molecular mechanism underlying cardiac hypertrophy?1. Ca2+ transients triggered by comparable LCC currents are decreased in amplitude and slowed in heart failure2. Compensated hypertrophy shows that the cellular aspects of E-C coupling appear to be normalThe molecular details underlying defective E-C coupling remain unknownWhether and when the intermolecular process of CICR is modified第4页/共22页 AASPressure-Overload Hypertrophy Model Induced by Aortic StenosisHypertrophy4~7 weeks第5页/共22页 50 ?m-70 mV0 mV, 300 ms200 ms1 cmPWDControlDHT*****CHT*Characterize the Cellular E-C Coupling第6页/共22页 ******** RP+70mvRP RP+70mv100 ms RPLCC-RyR Coupling During HypertrophyPercentage of Ca2+ sparks triggered by the first Ca2t sparkletsPercentage of depolarization pulses that occurred without triggering any Ca2+ sparks第7页/共22页 50 msCoupling latencyControlCHTDHT***Kinetics of LCC-RyR Coupling**Time constant for LCC-RyR coupling第8页/共22页 How Is LCC-RyR Intermolecular Failure Linked to the Global Performance of E-C Coupling?第9页/共22页 Ca2+ spikes tended to be desynchronizedgihdefabc-70 mV0 mV10 ?mControlCHTDHTA50 ms20?F/F0BDspikeadgbehcfi****ControlCHTDHTTime delay fromdepolarization to the peak of each Ca2+ spike第10页/共22页 **Cellular Tolerance Against Intermolecular Failure第11页/共22页 Numerical Simulation of Stability Marginstability marginstability margin extendedN C D F第12页/共22页 Seeking Potential Mechanisms Underlying the Intermolecular Failure?第13页/共22页 SR Ca2+ Load in Resting Cells第14页/共22页 A LCC RyR OverlayCon CHT DHT BLCC-RyR Overlapping020406080100 (%)ControlCHTDHTStructural Arrangement between SR and Cell/T-tubule第15页/共22页 00.020.040.060.080.100.12ShamCHTmRNA expression(JP-2/GAPDH)**Junctophilin2CaLCCRyrSRCa12 nmPotential Mechanism of Intermolecular Failure第1