ROS in diabetic atria regulate SK2 degradation by Atrogin-1 through the NF-κB signaling pathway

作者：Jian Xu, Dong Zhang, Yibo Ma, Hui Du, Yi Wang, Wenping Luo, Ruxing Wang, Fu Yi · 发表于：Journal of Biological Chemistry · 年份：2024 · DOI：10.1016/j.jbc.2024.105735 · 被引用次数：9 · 研究领域：NF-κB Signaling Pathways、Cardiac Fibrosis and Remodeling、RNA regulation and disease

One of the independent risk factors for atrial fibrillation (AF) is diabetes mellitus (DM); however, the underlying mechanisms causing AF in DM are unknown. Our previous investigation indicated that the muscle-specific E3 ligase Atrogin-1 contributes to SK2 protein degradation in the atria of streptozotocin (STZ)-induced DM mice, increasing susceptibility to atrial arrhythmias. However, the underlying mechanism of Atrogin-1-mediated SK2 degradation and associated signaling pathways are unclear. The aim of this study was to elucidate the relationship among ROS, the NF-κB signaling pathway, and Atrogin-1 protein expression in the atrial myocardia of DM mice. We found that SK2 expression was downregulated comitant with increased reactive oxygen species (ROS) generation and enhanced NF-κB signaling activation in the atrial cardiomyocytes of DM mice. These observations were mimicked by exogenously applicating H 2 O 2 and by high glucose (HG) culture conditions in HL-1 cells. Inhibition of ROS production by diphenyleneiodonium chloride (DPI) or silencing of NF-κB by siRNA decreased the protein expression of NF-κB and Atrogin-1 and increased that of SK2 in HL-1 cells with HG culture. Moreover, chromatin immunoprecipitation (ChIP) assay demonstrated that NF-κB/p65 directly binds to the promoter of the FBXO32 gene (encoding Atrogin-1), regulating the FBXO32 transcription. Finally, we evaluated the therapeutic effects of curcumin, known as a NF-κB inhibitor, on Atrogin-1 and SK2 expres...