The Role And Mechanism Of Mechano-sensitive Ion Channel Piezo1 In Pathological Cardiac Hypertrophy And Arrhythmia

Background: Pathological cardiac hypertrophy is the major pathological change of ventricular remodeling,featured by cardiomyocyte hypertrophy,increased heart mass,cardiac fibrosis,eventually leading to heart failure.Beyond neurohumoral regulation,mechanical stress induced by hemodynamic change also triggers pathological cardiac hypertrophy.Piezo1 is a novel mechanosensitive ion channel,which is sensitive to various mechanical stress and has been reported to participate in several pathophysiological processes.However,the role of Piezo1 in stress-induced cardiac hypertrophy remains unknown.Methods and results: We identified cardiac Piezo1 was remarkably upregulated in mice subjected to transverse aortic constriction（TAC）and enriched in intercalated disks of cardiomyocytes,by using RT-PCR,western blot and immunohistochemistry staining.Through applying cardiac conditional Piezo1 knockout mice（Piezo1Cko）undergoing transverse aortic constriction（TAC）,we demonstrated that Piezo1 deletion in cardiomyocytes attenuated the development of TAC-induced cardiac hypertrophy and subsequent adverse fibrosis and heart failure in terminal stage.Piezo1 deletion in cardiomyocytes also significantly decreased the Ca²⁺ transient amplitude induced by isoproterenol stimulation.Activation of Piezo1,by its agonist Yoda1,led to the enlargement of neonatal rat cardiomyocytes（NRCMs）and the activation of fetal gene program,which was blocked by Piezo1 silencing,Yoda1 antagonist Dooku1 and Piezo1 non-specific inhibitor Gsm Tx4.Through whole genome sequencing and further in vitro experiments,we found that the activation of Piezo1 perturbed calcium homeostasis by enhancing extracellular Ca²⁺ influx,thereby activating Ca²⁺-dependent calcineurin and calpain signaling.Inhibiting calcineurin or calpain,by either Cyclosporin A or PD 150606,abolished Yoda1-induced hypertrophic growth of cardiomyocytes in vitro.Conclusions: This study characterizes an undefined role of Piezo1 in exacerbating pathological cardiac hypertrophy through calcineurin and calpain related calcium pathways,implying a promising therapeutic target for cardiac hypertrophy.Background: Myocardial infarction is a main cause of heart failure and sudden cardiac death,which is accompanied by cardiomyocyte death,cardiac fibrosis,as well as cardiac electrical remodeling.Myocardial infarction alters the mechanical tension of the ventricular wall,as well as the expression and distribution of mechano-sensitive ion channels in cardiomyocytes.These alterations contribute to the abnormality of the cardiac electrical conduction activity,which is the major mechanism of ventricular electrical remodeling after myocardial infarction.Piezo1,as an important mechanical stresssensitive ion channel with preference to Ca2+,participate in the regulation of calcium homeostasis in cells.But its role in ventricular electrical remodeling after myocardial infarction is still unclear.Methods and results: Using western blot and immunohistochemistry staining,we demonstrated that the expression of Piezo1 significantly increased in the hearts of patients during end-stage of heart failure.We found that the Piezo1 deletion in cardiomyocytes（Piezo1CKO）attenuated cardiac dysfunction and significantly reduced the mortality induced myocardial infarction.Further,Piezo1 knockout in cardiomyocytes significantly reduced the occurrence of malignant arrhythmias induced by intracardiac programmed electrical stimulation after myocardial infarction.In human induced pluripotent stem cells derived cardiomyocytes（hi PSC-CM）,we found that Piezo1 activation by its specific agonist Yoda1 significantly shortened the duration of action potentials,which increase the risk of arrhythmia.Further experiments confirmed that continuous activation of Piezo1 induced early depolarization of action potential,which was the electrophysiological foundation for the malignant arrhythmia.Conclusions: We found,for the first time,that the mechanosensitive ion channel Piezo1 handled the occurrence of arrhythmia after myocardial infarction,which was attributed by the generation of continuous early depolarization of action potential.