DIPHENYLENE IODONIUM INHIBITS THE INDUCTION OF ERYTHROPOIETIN AND OTHER MAMMALIAN GENES BY HYPOXIA - IMPLICATIONS FOR THE MECHANISM OF OXYGEN SENSING

Recent studies on the induction of erythropoietin gene expression by h ypoxia have indicated that erythropoietin forms part of a widely opera tive system of gene regulation by oxygen. Similar responses to hypoxia , cobaltous ions and desferrioxamine have indicated that the action of these agents is closely connected with the mechanism of oxygen sensin g. To consider further the mechanisms underlying these responses, the effect of iodonium compounds was tested on five genes which show oxyge n-regulated expression; erythropoietin, vascular endothelial growth fa ctor (VEGF), lactate dehydrogenase-A (LDH-A), glucose transporter-1 (G LUT-1) and placental growth factor (PLGF). In each case, the response to hypoxia was specifically inhibited by low doses of diphenylene iodo nium (Ph(2)I(+)). This occurred irrespective of whether the hypoxic re sponse was induction of gene expression (erythropoietin, vascular endo thelial growth factor, lactate dehydrogenase-A, glucose transporter-1) or inhibition of gene expression (PLGF). In contrast, the induction o f gene expression by cobaltous ions or desferrioxamine was not inhibit ed by Ph(2)I(+). The differential action of Ph(2)I(+) on the response to hypoxia versus the response to cobaltous ions or desferrioxamine mu st reflect a difference in the mechanism of action of these stimuli, w hich will require accommodation in any model of the oxygen-sensing mec hanism. Based on the known properties of Ph(2)I(+), the implication of these findings is that the mechanism of oxygen sensing most probably involves the operation of a flavoprotein oxidoreductase.