Abstract Body: Background: Atherosclerosis-related cardiovascular diseases (CVD) remain the leading cause of death worldwide. Current therapies mainly focus on managing the risk of atherosclerosis rather than directly targeting the plaque-causing cells. Epigenetics and metabolism often occur early in various diseases, and their close interaction has led to the emergence of the concept of “metabolo-epigenetics.” Yet, the precise mechanisms by which they control transcriptomic and phenotypic changes in atherosclerosis remain unclear. Global changes in epigenome are driven in part by the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex. We previously demonstrated that BAF60c, a subunit of SWI/SNF, is essential for preserving vascular smooth muscle cell (VSMC) contractile phenotype. Here, we will investigate the key role of BAF60c-dependent metabolo-epigenetics in VSMC biology and atherosclerosis.
Methods and Results: Analysis of scRNA-seq data revealed that BAF60c is the most abundant BAF60 subunit, selectively expressed in VSMC within the normal aortic wall, and its expression was time-dependently decreased in the atherosclerotic aorta of mice. A decrease in BAF60c was also observed in human atherosclerotic lesions. Using male SMC-specific Baf60c knockout mice in an Apoe^-/- background (Baf60c^SMKO-Apoe^-/-) and a Western diet (WD)-induced atherosclerosis model, we observed a significant increase in atherosclerotic burden in Baf60c^SMKO-Apoe^-/- mice compared with littermate controls. Using gain- and loss-of-function approaches, combined with RNA-seq, metabolic analysis, ChIP-assays, and fluorescence staining, we discovered that BAF60c inhibits VSMC metabolic reprogramming, oxidative stress and the transition to macrophage-like and foamy cell phenotypes. Notably, knockdown of BAF60c enhances glycolysis-driven histone lactylation, which couples the metabolic and phenotypic states of VSMC with chromatin organization.
Conclusion: BAF60c protects against atherogenesis through metabolo-epigenetic modulation of VSMC homeostasis. This finding paves the way for future research to advance and deepen our understanding of metabolo-epigenetic mechanisms in CVD.