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bioRxiv · 10.1101/2024.11.26.625561

CEACAM1 Targets ABCA1 to Mediate Atrial Fibrillation via Lipophagy-Dependent Ferroptosis

Hu, W.-w.·Zou, J.-h.·Li, Z.-x.·Yang, B.-n.·Ma, X.·Zhou, R.·Pu, J.·Wang, J.·Zhao, L.
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Abstract

Atrial fibrillation (AF) is one of the most common arrhythmias, imposing a significant burden on individuals due to its association with cerebrovascular events. The mechanisms underlying AF involve cardiac structural remodeling, electrical remodeling, and metabolic remodeling, with oxidative stress playing a crucial role. Our previous studies demonstrated that upregulation of CEACAM1 can increase oxidative stress, inhibit cell proliferation, and potentially contribute to cellular damage, while ferroptosis is closely associated with AF. In this study, we observed a significant increase in CEACAM1 expression in an AF model. Knocking out CEACAM1 revealed changes in mitochondrial membrane potential, reactive oxygen species (ROS) levels, intracellular Ca2+ concentration, channel proteins, and glycolipid metabolic enzymes. This knockout reversed electrical, structural, and metabolic remodeling in AF. Further investigation showed that CEACAM1 knockout inhibited ferroptosis, as evidenced by ferroptosis-related indicators. Using colocalization analyses of lipid droplets, lysosomes, and autophagosomes, we discovered that CEACAM1 knockout suppressed autophagy and lipophagy during AF. Supplementation with free fatty acids (FFAs) in the AF model post-CEACAM1 knockout suggested that the inhibition of ferroptosis was linked to a reduction in FFAs. Transcriptomic and non-targeted metabolomic analyses, along with ABCA1 interference studies, indicated that CEACAM1 knockout mitigates AF by promoting ABCA1 expression. In summary, CEACAM1 targets ABCA1 to alleviate AF through the regulation of lipophagy-dependent ferroptosis, as demonstrated in both cellular and animal models. BackgroundFerroptosis is a regulated form of cell death, but its connection with atrial fibrillation(AF) remains unclear. Since CEACAM1 knockout reduces oxidative stress and protects cells, we investigated the relationship among CEACAM1, ferroptosis, and AF to uncover the regulatory mechanisms of ferroptosis in AF. MethodsWe established AF models using HL-1 cells, human pluripotent stem cells, and rats. CEACAM1 expression levels were assessed in these models, along with changes in mitochondrial membrane potential, ROS levels, intracellular Ca2+ concentration, channel proteins, glycolipid metabolic enzymes, and ferroptosis-related indicators following CEACAM1 knockout. Through transcriptomics, non-target metabolomics, and immunoprecipitation screening, we identified ABCA1 as a downstream gene of CEACAM1 involved in protecting against AF. Subsequently, ABCA1 interference experiments were conducted, and colocalization analyses of lipid droplets, lysosomes, and autophagosomes were performed after the application of ferroptosis activators, lipophagy inhibitors, and lipophagy activators. FFAs were added to the AF model to evaluate changes in lipophagy and ferroptosis following CEACAM1 knockout. ResultsIn the AF model using HL-1 myocytes, CEACAM1 knockout reverse electrical, structural, and metabolic remodeling while inhibiting ferroptosis, with ABCA1 as a downstream gene. In the AF model derived from pluripotent stem cells differentiated into atrial myocytes, CEACAM1 knockout suppressed autophagy and lipophagy during AF, thereby inhibiting ferroptosis, which correlated with reduced FFA release. This process was regulated by ABCA1. In the rat AF model, ABCA1, identified as a downstream gene of CEACAM1, was further confirmed to inhibit ferroptosis by regulating FFA levels. ConclusionThis study reveals that CEACAM1 knockout inhibits ferroptosis in AF models by upregulating ABCA1 and reducing FFA levels, providing a novel regulatory mechanism for ferroptosis in AF. O_FIG O_LINKSMALLFIG WIDTH=172 HEIGHT=200 SRC="FIGDIR/small/625561v1_ufig1.gif" ALT="Figure 1"> View larger version (57K): org.highwire.dtl.DTLVardef@809c82org.highwire.dtl.DTLVardef@1a339d6org.highwire.dtl.DTLVardef@12a20d4org.highwire.dtl.DTLVardef@d14927_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Hu, W.-w., Zou, J.-h., Li, Z.-x., Yang, B.-n., Ma, X., Zhou, R., Pu, J., Wang, J., Zhao, L.. 2024-12-02. CEACAM1 Targets ABCA1 to Mediate Atrial Fibrillation via Lipophagy-Dependent Ferroptosis. https://doi.org/10.1101/2024.11.26.625561

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