Cardiac Piezo1 Exacerbates Lethal Ventricular Arrhythmogenesis by Linking Mechanical Stress with Ca2+ Handling after Myocardial Infarction

ABSTRACT: Aims: Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). 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 MI remains undefined. We aimed to examine the impact of increased mechanical stress and identify the role of a key sensor Piezo1 in ventricular arrhythmogenesis in MI. Methods and Results: Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the mostly 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 MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with significantly 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 regulated Ca2+ transient and affected SERCA2 and phosphorylated-RyR2 expressions, Piezo1 knockout in cardiomyocyte significantly influenced the expression of calcium ion binding and ion transport-related genes, including the expression of calcium/calmodulin-dependent protein kinase II (CaMKII) and Calpains, leading to the alteration of Ca2+-related signaling and impaired intracellular calcium cycling dynamics., leading to impaired intracellular calcium cycling dynamics. Furthermore, in human induced-pluripotent stem cell derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling through significantly shortening the duration of action potential, inducing early afterdepolarization and enhancing triggered activity. Conclusion: This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved through regulating Ca2+ handling, implying a promising therapeutic target in sudden cardiac death and heart failure.

ORGANISM(S): Mus musculus

PROVIDER: GSE230042 | GEO | 2025/04/30

REPOSITORIES: GEO