Article ID Journal Published Year Pages File Type
2536786 European Journal of Pharmacology 2006 5 Pages PDF
Abstract

We investigated the role of Ca2+-independent phospholipase A2 (iPLA2) as well as cytosolic phospholipase A2 (cPLA2) in hypoxia-inducible factor-1 (HIF-1)-dependent gene expression. An inhibitor of both iPLA2 and cPLA2, methyl arachidonyl fluorophosphonate (MAFP), prevented hypoxia-induced erythropoietin mRNA expression without affecting HIF-1α accumulation in Hep3B cells. The DNA-binding of HIF-1α was suppressed by MAFP as confirmed by luciferase reporter gene assays with the hypoxia response element. Translocation of HIF-1α to the nucleus assessed by its presence in the nuclear extracts of cells exposed to hypoxia, was diminished by MAFP. However, hypoxia-dependent gene expression was not affected in mesangial cells obtained from cPLA2α null mice. Furthermore, a specific iPLA2 inhibitor, bromoenol lactone, suppressed erythropoietin mRNA expression and HIF-1α translocation to the nucleus under hypoxic conditions. Thus, iPLA2, but not cPLA2α, may play an important role in regulating the transport of HIF-1α to the nucleus.

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