Visinin-like protein 1 disrupts calcium homeostasis and promotes atrial fibrillation in human and rodent models

Le résumé fourni par la source

Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular Ca 2+ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating Ca 2+ signaling, yet its role in AF remains undefined. In this study, we integrated bulk RNA sequencing, single-cell transcriptomics, and electrophysiological profiling from human AF patients and rodent AF models to identify VILIP-1 as a key mediator of Ca 2+ dysregulation in AF. VILIP-1 was significantly upregulated in atrial tissues from AF patients and in pacing-induced rat AF models, with enhanced membrane localization in cardiomyocytes. Atrial cardiomyocyte-specific overexpression of VILIP-1 led to pathological Ca 2+ leakage, promoting delayed afterdepolarizations (DADs) and action potential duration (APD) alternans, which fostered AF substrate formation and increased arrhythmia susceptibility. Mechanistically, VILIP-1 augmented the surface abundance of sodium-calcium exchanger 1 (NCX-1) via a myristoylation-dependent trafficking mechanism, thereby disrupting Ca 2+ handling and initiating AF. Pharmacologically, repaglinide and desloratadine, two FDA-approved drugs that identified to target VILIP-1 or its myristoylation, attenuated AF susceptibility by reducing NCX-1 surface expression and restoring intracellular Ca 2+ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial Ca 2+ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.

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