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Effects of adenovirus mediated GLA expression on gene expression of hiPSC-derived ventricular cardiomyocytes from control and Fabri Disease Lines

ABSTRACT: Fabry disease is an X-linked lysosomal storage disorder caused by loss-of-function mutations in GLA, resulting in α-galactosidase A deficiency and glycosphingolipid accumulation that contributes to systemic disease including kidney disease, stroke, and cardiac arrhythmias. To model Fabry-associated arrhythmogenesis, we generated hiPSC-derived ventricular cardiomyocytes (hiPSC-VCMs) from patient and control iPSCs and compared electrophysiology, calcium transients, and gene expression profiles between groups. Fabry hiPSC-VCMs displayed intrinsic chaotic arrhythmias and abnormal calcium handling along with dysregulated transcription of genes encoding ion channels. To assess the impact of restoring enzyme activity, both control and Fabry hiPSC-VCMs were infected with an adenovirus to drive GLA overexpression, and GLA restoration did not prevent complex arrhythmias or normalize ion-channel gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE327944 | GEO | 2026/05/15

REPOSITORIES: GEO

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Project description: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 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 MI. 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 MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI 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.

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Effects of adenovirus mediated GLA expression on gene expression of hiPSC-derived ventricular cardiomyocytes from control and Fabri Disease Lines

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