Abstract 18399: Loss of Myeloid Epigenetic-Metabolic Crosstalk by BAF60a Deficiency Aggravates Atherosclerosis

Abstract

Introduction: Atherosclerosis is a primary medical concern, characterized by the involvement of immune cells within atherosclerotic plaques. Notably, the modulation of gene expression through chromatin remodeling and transcription machinery, known to be disrupted in disease conditions, is less studied in macrophages within atherosclerotic plaques. Hypothesis: We propose that BAF60a , a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex, might be instrumental in atherosclerosis by modulating disease-specific epigenetic-metabolic crosstalk, offering a potential therapeutic avenue. Methods: To evaluate our hypothesis, we assessed BAF60a expression in macrophages derived from advanced plaques. To decipher its role, myeloid Baf60a was deleted in mice with hypercholesterolemic ApoE deficient backgrounds. Subsequent changes in atherosclerotic lesion size, mitochondrial integrity, cellular adhesion, and apoptosis were characterized. ChIP-seq and ATAC-seq were employed to analyze the function of BAF60 a in maintaining key transcription factor activities. Results: Our results revealed a marked downregulation of BAF60a in macrophages from advanced plaques. Upon myeloid Baf60a deletion, we observed compromised mitochondrial integrity, increased cellular adhesion, enhanced apoptosis, and amplified plaque formation. Importantly, BAF60a was crucial in preserving mitochondrial energy homeostasis in the face of pro-atherogenic stimuli, as it sustained Nuclear Respiratory Factor 1 ( NRF1 ) access to critical genes. BAF60a overexpression rescued these defects in an NRF1-dependent manner. Conclusions: We conclude that the BAF60a-NRF1 axis is a key regulator of mitochondrial function in atherosclerosis. Our study underscores the potential of restoring the disrupted epigenetic-metabolic crosstalk as a promising therapeutic strategy in treating atherosclerosis.