Abstract Body: BACKGROUND: The phenotypic switching of vascular smooth muscle cells (VSMCs) plays a crucial role in atherosclerosis. However, the epigenetic mechanisms regulating the inflammatory transition of VSMCs remain largely unexplored, and the specific role of the chromatin remodeler INO80 in atherosclerosis is unclear.
METHODS: We combined analyses of human atherosclerotic samples, VSMC-specific genetic mouse models, immunoprecipitation-mass spectrometry (IP-MS), and genomic approaches including single-cell RNA-seq, ATAC-seq, and Cut&Tag to define the function and mechanism of INO80.
RESULTS: The single-cell RNA-seq analysis of human coronary atherosclerotic plaques revealed elevated INO80 expression in inflammatory VSMCs during disease progression. VSMC-specific Ino80 deletion markedly attenuated atherosclerosis development in mice. Mechanistically, INO80 physically interacts with the IKKβ-p65 complex. This interaction cooperatively enhances chromatin accessibility of inflammatory genes, such as IL6, IL1B, CXCL1, and promotes their transcription. Furthermore, we uncovered a kinase-independent nuclear role for IKKβ in directly recruiting the INO80 chromatin remodeler to inflammatory genes to facilitate transcriptional activation.
CONCLUSIONS: The INO80-dependent chromatin remodeling acts as a central epigenetic driver of VSMC inflammatory switching in atherosclerosis. Our findings define a novel signaling-epigenetic axis (INO80-IKKβ-p65) as a critical regulatory mechanism and a potential therapeutic target for atherosclerotic disease.