Atrial cardiomyocyte-specific overexpression of VILIP-1 significantly increased pacing-induced atrial fibrillation susceptibility in mice compared to controls (55.6% vs 0%, p=0.0337).
Does targeting VILIP-1 with repaglinide or desloratadine improve calcium homeostasis and prevent atrial fibrillation in preclinical models?
VILIP-1 is a novel upstream regulator of atrial calcium homeostasis, and its pharmacological inhibition with repaglinide represents a promising therapeutic strategy for atrial fibrillation.
Absolute Event Rate: 55.6% vs 0%
p-value: p=0.0337
Atrial fibrillation (AF), the most prevalent sustained cardiac arrhythmia, is closely linked to disturbed intracellular Ca2+ homeostasis. Visinin-like protein 1 (VILIP-1), newly identified in cardiomyocytes, has been implicated in modulating Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ homeostasis. Collectively, our findings define VILIP-1 as a critical upstream modulator of atrial Ca2+ homeostasis and establish it as a promising therapeutic target for AF, with efficacy validated in human and rodent models.
Xiong et al. (Mon,) conducted a other in Atrial fibrillation. VILIP-1 overexpression vs. Control was evaluated on Incidence of pacing-induced atrial fibrillation (p=0.0337). Atrial cardiomyocyte-specific overexpression of VILIP-1 significantly increased pacing-induced atrial fibrillation susceptibility in mice compared to controls (55.6% vs 0%, p=0.0337).