Abstract 399: Oxidized Phospholipids Regulate Inflammatory Gene Transcription via Bromodomain Containing 4 (BRD4) In Vascular Endothelial Cells

Objective: Atherosclerosis is a chronic inflammatory disease initiated by monocyte infiltration into the vessel wall. Oxidized phospholipids (Ox-PL) that accumulate in the subendothelial space during hyperlipidemia elicit changes in inflammatory gene transcription and endothelial cell function. Bromodomain-containing 4 (BRD4) reads histone acetyl epigenetic modification and regulates inflammatory gene transcription controlled by the modification in the endothelial cells. In this study, we tested whether oxidized phospholipids regulates inflammatory gene transcription via histone acetyl epigenetic modification and its reader BRD4 in vascular endothelial cells. Methods and Results: A representative Ox-PL, Ox-PAPC (oxidized 1-palmitoyl-2-arachidonoyl-sn-glycerol-3-phosphatidylcholine), regulates over 1,500 transcripts in human aortic endothelial cells (HAECs) including inflammatory IL-8 and monocyte chemoattractant protein 1 (MCP1). Gene silencing of histone acetyl transferases (HATs) p300 and CBP also inhibited transcription of inflammatory genes in endothelial cells, suggesting that the histone acetyl epigenetic modification are involved in inflammatory gene transcription by Ox-PAPC. Small molecule inhibitors of BRD4 or BRD4 gene silencing potently and selectively repressed inflammatory gene transcription by Ox-PAPC. Microarray analysis revealed that the inhibitor downregulated hundreds of genes involved in inflammation and apoptosis. The administration of the BRD4 inhibitor JQ1(+) in LDLR null mouse showed a significant inhibition of the inflammatory responses induced by hyperlipidemia in the vascular system. Conclusion: Histone acetyl epigenetic modification and the reader BRD4 mediates inflammatory gene transcription by oxidized phospholipids in the endothelial cells. Targeting of BRD4 may be an efficient approach to prevent hyperlipidemia-induced inflammation and atherosclerosis.