An Epoxyisoprostane Is a Major Regulator of Endothelial Cell Function

• DOI: 10.1021/jm400959q
• Publication Date: 2013-10-13T14:39:54Z
• Authors: Wei Zhong; James R. Springstead; Ramea Al-Mubarak; Sangderk Lee; Rongsong Li; Benjamin Emert; Judith A. Berliner; Michael E. Jung
• Keywords: Structure-Activity Relationship; 0303 health sciences; 03 medical and health sciences; Dose-Response Relationship, Drug; Anti-Inflammatory Agents, Non-Steroidal; Interleukin-1beta; Molecular Conformation; Endothelial Cells; Humans; Isoprostanes; 3. Good health

The goal of these studies was to determine the effect of 5,6-epoxyisoprostane, EI, on human aortic endothelial cells (HAEC). EI can form as a phospholipase product of 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine, PEIPC, a proinflammatory molecule that accumulates in sites of inflammation where phospholipases are also increased. To determine the effect of EI on HAEC, we synthesized several stereoisomers of EI using a convergent approach from the individual optically pure building blocks, the epoxyaldehydes 5 and 6 and the bromoenones 14 and 16. The desired stereoisomer of EI can be prepared from these materials in only six operations, and thus, large amounts of the product can be obtained. The trans/trans isomers had the most potent activity, suggesting specificity in the interaction of EI with the cell surface. EI has potent anti-inflammatory effects in HAEC. EI strongly inhibits the production of MCP-1, a major monocyte chemotactic factor, and either decreases or minimally increases the levels of 10 proinflammatory molecules increased by PEIPC. EI also strongly down-regulates the inflammatory effects of IL-1β, a major inflammatory cytokine. Thus EI, a hydrolytic product of PEIPC, has potent anti-inflammatory function.