KMT2B drives inflammation in endothelial cells and promotes atherosclerosis via histone H3 lysine 4 trimethylation-mediated autophagy.

Atherosclerosis is a chronic condition characterized by persistent inflammation and vascular remodeling. Oxidized low-density lipoprotein (ox-LDL) plays a central role in this process by promoting inflammation and inducing epigenetic modifications. This study aimed to investigate the role of KMT2B, a histone methyltransferase, in regulating inflammation and autophagy in endothelial cells (ECs) during atherosclerosis. ApoE-/- mice were fed a western diet for 2, 4, 8, and 12 weeks to assess epigenetic modifications during atherosclerosis. In vitro, rat aortic endothelial cells (RAECs) and human aortic endothelial cells (HAECs) were exposed to ox-LDL at various time points. To study the role of KMT2B in inflammation, small-interfering RNA-mediated knockdown and plasmid overexpression were employed to manipulate KMT2B expression in RAECs and HAECs. In vivo, Kmt2b was knocked down using lentivirus-expressed sgKmt2b in ApoE-/- mice, and its impact on atherosclerotic plaque formation, lipid accumulation, and inflammatory cytokines was evaluated. To explore the mechanism by which ox-LDL regulates the expression of KMT2B, reactive oxygen species (ROS) levels were detected, and siSyk and siFos were performed in RAECs. Western diet feeding of ApoE-/- mice resulted in elevated KMT2B expression and H3K4me3 levels in atherosclerotic plaques, particularly in ECs and macrophages. KMT2B was found to directly regulate autophagy, followed by the regulation of inflammation. Furthermore, inhibiting the expression of KMT2B in ApoE-/- mice improved atherosclerosis and suppressed inflammation. The transcription factor Fos mediated KMT2B expression through Syk- and ROS-dependent signaling, enhancing its binding to the Kmt2b promoter region. KMT2B is a critical regulator of autophagy and inflammation in atherosclerosis, with Fos-mediated signaling driving its expression. Targeting KMT2B may offer a promising therapeutic strategy for modulating inflammation and plaque progression in atherosclerosis.