An Epoxyisoprostane Is a Major Regulator of Endothelial Cell Function

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.