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1、Early Molecular Mechanism UnderlyingCardiac HypertrophyYouyi Zhang Institute of Vascular Medicine Peking University Third Hospital12 nm电压依赖L型钙通道Ca2+Ca2+LCCRyRSR钙池Pathological factorsHormonesNeurotransmittersCytokinesForceFunction maintenanceHeart failureCa2Ca2Early molecular mechanism underlying car
2、diac 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 a
3、nd when the intermolecular process of CICR is modifiedAASPressure-Overload Hypertrophy Model Induced by Aortic StenosisHypertrophy47 weeks50 m-70 mV0 mV, 300 ms200 ms1 cmPWDControlDHT*CHT*Characterize the Cellular E-C Coupling* *RP+70mv RPRP+70mv100 msRPLCC-RyR Coupling During HypertrophyPercentage
4、of Ca2+ sparks triggered by the first Ca2t sparkletsPercentage of depolarization pulses that occurred without triggering any Ca2+ sparks50 msCoupling latencyControlCHTDHT*Kinetics of LCC-RyR Coupling*Time constant for LCC-RyR couplingHow Is LCC-RyR Intermolecular Failure Linked to the Global Perform
5、ance of E-C Coupling?Ca2+ spikes tended to be desynchronizedgihdefabc-70 mV0 mV10 mControlCHTDHTA50 ms20F/F0BDspike adgbehcfi*ControlCHTDHTTime delay from depolarization to the peak of each Ca2+ spike*Cellular Tolerance Against Intermolecular FailureNumerical Simulation of Stability Marginstability
6、marginstability margin extendedN C D FSeeking Potential Mechanisms Underlying the Intermolecular Failure?SR Ca2+ Load in Resting CellsALCC RyR OverlayCon CHT DHT BLCC-RyR Overlapping020406080100(%)Control CHT DHTStructural Arrangement between SR and Cell/T-tubule00.020.040.060.080.100.12ShamCHTmRNA
7、expression (JP-2/GAPDH)*Junctophilin2CaLCCRyrSRCa12 nmPotential Mechanism of Intermolecular FailureResearch HighlightThese results suggest that in heart failure, there is a state of intermolecular failure that proceeds without altering cellular function. So, targeting this period at a very early sta
8、ge of the condition suggests perhaps by LCC inactivation or regulation of junctophilin mightbe beneficial in the prevention of heart failure. Nature Reviews Drug Discovery 2007.4致致 谢谢￥: 科技部“973”计划国家自然科学基金委北京大学生命科学院 王世强 课题组 北京大学第三医院 张幼怡 课题组Experimental Support of Stability MarginMorphology of Ventricular Muscle Cells in Cardiac HypertrophyHypertrophy is the important pathological basis for the heart failure.Characterize the Cellular E-C Coupling50 m-70 mV0 mV, 300 msCon CHT DHT
