首页|Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca2+ Handling After Myocardial Infarction
Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca2+ Handling After Myocardial Infarction
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Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction(Ml).Accumulating data show that ischemia,sympathetic activation,and inflammation contribute to arrhythmogenesis.However,the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following Ml remain undefined.We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in Ml.Concomitant with increased ventricular pressure,Piezo1,as a newly recognized mechano-sensitive cation channel,was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure.Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes,which are responsible for intracellular calcium homeostasis and intercellular communication.Cardiomyocyte-conditional Piezo1 knockout mice(Piezo1Cko)exhibited preserved cardiac function after Ml.Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after Ml with a markedly reduced incidence of ventricular tachycardia.In contrast,activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment.Mechanistically,Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+overload and increasing the activation of Ca2+-modulated signaling,CaMKⅡ,and calpain,which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+leaking,finally provoking cardiac arrhythmias.Furthermore,in human induced pluripotent stem cell-derived cardiomyocytes(hiPSC-CMs),Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential,inducing early afterdepolarization,and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling,which is achieved by regulating Ca2+handling,implying a promising therapeutic target in sudden cardiac death and heart failure.
Department of Cardiology,Cardiovascular Key Laboratory of Zhejiang Province,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China
Department of Endocrinology,The Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou 310009,China
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