HDAC3 activates endothelial NLRP3 inflammasome and promotes atherosclerosis via inhibiting the acetylation of specificity protein 1

Histone deacetylase 3 (HDAC3) is an epigenetic modifying enzyme closely linked to the development of atherosclerosis. Endothelial inflammation is a critical factor in atherosclerosis. However, the role of HDAC3 in mediating epigenetic modifications and regulating endothelial inflammation in atherosclerosis remains unclear. This study aims to investigate the impact of HDAC3 on endothelial inflammation and its contribution to atherosclerosis. Firstly, single-cell transcriptomic analysis identified elevated expression of HDAC3 and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) in inflammatory endothelial cells of atherosclerotic plaques in symptomatic patients. Endothelial-specific knockout HDAC3 in an Apolipoprotein E knockout (apoE^-/-) mice decreased atherosclerotic lesion by reducing lipid deposition and endothelial NLRP3 inflammasome activation compared with control mice. Consistently, experiments using HDAC3 Inhibitor and overexpression in human umbilical vein endothelial cells (HUVECs) demonstrated that HDAC3 enhanced the transcriptional upregulation of NLRP3 inflammasome by promoting nuclear factor kappa-B pathway, thereby contributing to the activation of the NLRP3 inflammasome and cellular injury. Further studies revealed that HDAC3 reduced specificity protein 1 (SP1) Lys-703 acetylation, thereby enhancing SP1 binding to the NLRP3 promoter and promoting NLRP3 transcription. Additionally, pharmacological inhibition of HDAC3 effectively ameliorated atherosclerosis by reducing endothelial inflammation and increasing SP1 acetylation in apoE^-/- mice. Thus, these findings demonstrate a crucial role of HDAC3 in endothelial inflammation and shed light on potential therapeutic strategy for atherosclerosis via inhibition of HDAC3.