Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in human aortic endothelial cell

Oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC) has been demonstrated to accumulate in atherosclerotic lesions and regulates expression of more than 1,000 genes in human aortic endothelial cell (HAEC). Among the most highly induced is heme oxygenase-1 (HO-1), a cell-protective antioxidant enzyme, which is sensitively induced by oxidative stress. To identify the pathway by which Ox-PAPC induces HO-1, we focused on the plasma membrane electron transport (PMET) complex, which contains ecto-NADH oxidase 1 (eNOX1) and NADPH:quinone oxidoreductase 1 (NQO1) and affects cellular redox status by regulating levels of NAD(P)H. We demonstrated that Ox-PAPC and its active components stimulated electron transfer through the in to by and to of the cell by of and to components and by We that Ox-PAPC of in in the of and by We that by Ox-PAPC which to the oxidative and of and Ox-PAPC oxidative and by we demonstrated that the in in the of cellular redox status and expression by Oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine (Ox-PAPC) has been demonstrated to accumulate in atherosclerotic lesions and regulates expression of more than 1,000 genes in human aortic endothelial cell (HAEC). Among the most highly induced is heme oxygenase-1 (HO-1), a cell-protective antioxidant enzyme, which is sensitively induced by oxidative stress. To identify the pathway by which Ox-PAPC induces HO-1, we focused on the plasma membrane electron transport (PMET) complex, which contains ecto-NADH oxidase 1 (eNOX1) and NADPH:quinone oxidoreductase 1 (NQO1) and affects cellular redox status by regulating levels of NAD(P)H. We demonstrated that Ox-PAPC and its active components stimulated electron transfer through the in to by and to of the cell by of and to components and by We that Ox-PAPC of in in the of and by We that by Ox-PAPC which to the oxidative and of and Ox-PAPC oxidative and by we demonstrated that the in in the of cellular redox status and expression by of the accumulate in the atherosclerotic lesions and the of in atherosclerotic lesions of and of of the is (Ox-PAPC) to cell of of the of a in We demonstrated that a Ox-PAPC regulates more than 1,000 and genes in human aortic endothelial cell of on of human endothelial cell to is of genes in endothelial genes to and redox status of on of human endothelial cell to is of genes in endothelial we active components of Ox-PAPC and the most active of of the of a in and and of in to We and that heme oxygenase-1 is induced by Ox-PAPC and in endothelial is of genes in endothelial expression of human heme oxygenase-1 of regulates antioxidant expression by in endothelial and in is sensitively induced by oxidative and has been to cell-protective and in endothelial to in human endothelial to expression of is by expression of human heme oxygenase-1 of in by heme and by the the of is 1 which is a of oxidative induces to and the of by oxidative of the antioxidant by of the the of oxidative in the and by Ox-PAPC in is that plasma membrane electron transport (PMET) a in by electron to the by a to cellular in cell the to the in cell cellular to the electron by the a the of cell is in the of cellular redox status by regulating levels in the membrane electron a has antioxidant and is the of and which antioxidant in the and in cellular and cell and has been to of ecto-NADH oxidase the of the plasma a in the and and oxidoreductase 1 (NQO1) the of plasma membrane membrane electron a of the plasma in plasma membrane electron of been ecto-NADH oxidase 1 and oxidase of the plasma to in the and a of cell a to in the cell oxidase and is by that is by has been that in endothelial that the by is a of plasma membrane electron transport the we demonstrated in Ox-PAPC the oxidative and to and and by and the of Ox-PAPC by and and of in to of the and and and and by of human is active in in and the of a of human aortic endothelial and in the of in 1 and by and to and the by the endothelial a in the of aortic endothelial by of of genes by and to and and and HO-1, and and cell in the is oxidative stimulated by on and endothelial a in the of aortic endothelial by of endothelial in the of by in in 1 and the and to in the the which transfer the electron to the the in the a the of cell in in and in of in the of electron and a a the of cell the the of in the of in the of and the the the of the to the electron a electron in in and in of in the and is membrane electron a of in by in the in of and of and the of in the of the of in the a in to in in in the and of the and to of the the the of the the of of and the of to the a in components of and a highly To the we electron which is a and a in cell cellular transfer to membrane electron a Ox-PAPC in the of by Ox-PAPC that is a of in the components of to a in which contains that in membrane electron a is of a of and on the of of oxidoreductase 1 in its plasma membrane and oxidoreductase 1 by in human in the of and and in the of in the levels of and in human aortic endothelial cell of in of in by of in the of which by of of in of in by of in the of which by of in a and induced by of Ox-PAPC and in the of electron of by in aortic endothelial the of and 1 and in the of Ox-PAPC and the levels of of the Ox-PAPC in Ox-PAPC electron the by the of of on more than that of the of Ox-PAPC a a in the of Ox-PAPC which to components of Ox-PAPC in the most induced more than of and in the in the Ox-PAPC and its and and its active components 1 and in the of levels of Ox-PAPC Ox-PAPC and levels of and 1 in and of Ox-PAPC 1 of the Ox-PAPC of components and in the of by to the of in of by we components by by by Ox-PAPC in the of by that Ox-PAPC in endothelial induces endothelial of that oxidative induced by We that induced of of cellular oxidative stress. is sensitively induced by oxidative we the of components on by by Ox-PAPC the of which is a and induced by Ox-PAPC in by Ox-PAPC in by Ox-PAPC by We the of the of which is of We on the to the of of the of the by to the of of by Ox-PAPC We that expression is by in the of and heme expression in to and levels of and in the to of induced by Ox-PAPC by in and and levels induced by Ox-PAPC by 1 and Ox-PAPC and levels induced by Ox-PAPC by to levels of in and and levels induced by Ox-PAPC by of oxidative and by Ox-PAPC in that the of in the the of oxidative by We the of on the of oxidative and expression by Ox-PAPC in in in the by that the of and in the by Ox-PAPC is is to in the the the through and oxidative in the oxidative and by Ox-PAPC in of by in Ox-PAPC the Ox-PAPC and levels by in and cell of cell of of a in the of by 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of to the to levels by to oxidative and is a of oxidase oxidative the in and in cell is antioxidant and in cellular and cell and in the the of Ox-PAPC by a of of the of and on by We that and in of on of human endothelial cell to endothelial a in the of aortic endothelial by of endothelial in the of by by of the and of the by which by Ox-PAPC We demonstrated that of in the of by Ox-PAPC to by We demonstrated that to and by Ox-PAPC most Ox-PAPC of by the to the in by in to to oxidative of demonstrated the of by oxidative stress. Ox-PAPC electron in and of on the of in to Ox-PAPC electron in the is in to by and of by Ox-PAPC in regulating expression by Ox-PAPC in that and in regulating in of endothelial expression of human heme oxygenase-1 of of heme oxygenase-1 in human is by of in the and and in the of Ox-PAPC to in the of the by Ox-PAPC is in the the of the been Ox-PAPC in and on the of electron NAD(P)H. that Ox-PAPC has a on the to the of electron and the of electron to by the of electron that Ox-PAPC the in the plasma membrane to the of electron the plasma membrane the We that Ox-PAPC of in the plasma membrane in in of endothelial by which membrane and of that the of the membrane membrane in of the of cell and of a of To on the of in membrane on the been that membrane is the of electron transport by in electron transport of electron transport of in and that the is by Ox-PAPC and in the of by Ox-PAPC through of that is of redox status in endothelial and a of in the of the accumulate in the atherosclerotic lesions and the of in atherosclerotic lesions of and of of the is (Ox-PAPC) to cell of of the of a in We demonstrated that a Ox-PAPC regulates more than 1,000 and genes in human aortic endothelial cell of on of human endothelial cell to is of genes in endothelial genes to and redox status of on of human endothelial cell to is of genes in endothelial we active components of Ox-PAPC and the most active of of the of a in and and of in to We and that heme oxygenase-1 is induced by Ox-PAPC and in endothelial is of genes in endothelial expression of human heme oxygenase-1 of regulates antioxidant expression by in endothelial and in is sensitively induced by oxidative and has been to cell-protective and in endothelial to in human endothelial to expression of is by expression of human heme oxygenase-1 of in by heme and by the the of is 1 which is a of oxidative induces to and the of by oxidative of the antioxidant by of the the of oxidative in the and by Ox-PAPC in is that plasma membrane electron transport (PMET) a in by electron to the by a to cellular in cell the to the in cell cellular to the electron by the a the of cell is in the of cellular redox status by regulating levels in the membrane electron a has antioxidant and is the of and which antioxidant in the and in cellular and cell and has been to of ecto-NADH oxidase the of the plasma a in the and and oxidoreductase 1 (NQO1) the of plasma membrane membrane electron a of the plasma in plasma membrane electron of been ecto-NADH oxidase 1 and oxidase of the plasma to in the and a of cell a to in the cell oxidase and is by that is by has been that in endothelial that the by is a of plasma membrane electron transport the we demonstrated in Ox-PAPC the oxidative and to and and by and the of Ox-PAPC by and and of in to of the and and and and by of human is active in in and the of a of human aortic endothelial and in the of in 1 and by and to and the by the endothelial a in the of aortic endothelial by of of genes by and to and and and HO-1, and and cell in the is oxidative stimulated by on and endothelial a in the of aortic endothelial by of endothelial in the of by in in 1 and the and to in the the which transfer the electron to the the in the a the of cell in in and in of in the of electron and a a the of cell the the of in the of in the of and the the the of the to the electron a electron in in and in of in the and is membrane electron a of in by in the in of and of and the of in the of the of in the a in to in in in the and of the and to of the the the of the the of of and the of to the a and and by and the of Ox-PAPC by and and of in to of the and and and and by of human is active in in and by and the of Ox-PAPC by and and of in to of the and and and and by of human is active in in and the of a of human aortic endothelial and in the of in 1 and and the of a of human aortic endothelial and in the of in 1 and by and to and the by the endothelial a in the of aortic endothelial by of of genes by 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in to a highly We demonstrated that Ox-PAPC of of the cell to the electron most active of stimulated in to the Ox-PAPC to the of to of the by of in the that the Ox-PAPC induced a in by to on in to has been to levels in the a to cellular in cell membrane electron a that by of endothelial Ox-PAPC and that oxidative induces endothelial of We in oxidative Ox-PAPC in of of and of by to levels in and we in the a which the of in by Ox-PAPC and in by Ox-PAPC by that of to the to levels by to oxidative and is a of oxidase oxidative the in and in cell is antioxidant and in cellular and cell and in the the of Ox-PAPC by a of of the of and on by We that and in of on of human endothelial cell to endothelial a in the of aortic endothelial by of endothelial in the of by by of the and of the by which by Ox-PAPC We demonstrated that of in the of by Ox-PAPC to by We demonstrated that to and by Ox-PAPC most Ox-PAPC of by the to the in by in to to oxidative of demonstrated the of by oxidative stress. Ox-PAPC electron in and of on the of in to Ox-PAPC electron in the is in to by and of by Ox-PAPC in regulating expression by Ox-PAPC in that and in regulating in of endothelial expression of human heme oxygenase-1 of of heme oxygenase-1 in human is by of in the and and in the of Ox-PAPC to in the of the by Ox-PAPC is in the the of the been Ox-PAPC in and on the of electron NAD(P)H. that Ox-PAPC has a on the to the of electron and the of electron to by the of electron that Ox-PAPC the in the plasma membrane to the of electron the plasma membrane the We that Ox-PAPC of in the plasma membrane in in of endothelial by which membrane and of that the of the membrane membrane in of the of cell and of a of To on the of in membrane on the been that membrane is the of electron transport by in electron transport of electron transport of in and that the is by Ox-PAPC and in the of by Ox-PAPC through of that is of redox status in endothelial and a of in the the of by levels been to by oxidative in a of We to identify the oxidative in Ox-PAPC of the we that the is a in of in to a highly We demonstrated that Ox-PAPC of of the cell to the electron most active of stimulated in to the Ox-PAPC to the of to of the by of in the We that the Ox-PAPC induced a in by to on in to has been to levels in the a to cellular in cell membrane electron a that by of endothelial Ox-PAPC and that oxidative induces endothelial of We in oxidative Ox-PAPC in of of and of by to levels in and we in the a which the of in by Ox-PAPC and in by Ox-PAPC by that of to the to levels by to oxidative and is a of oxidase oxidative the in and in cell is antioxidant and in cellular and cell and in the the of Ox-PAPC by a of of the of and on by We that and in of on of human endothelial cell to endothelial a in the of aortic endothelial by of endothelial in the of by by of the and of We the by which by Ox-PAPC We demonstrated that of in the of by Ox-PAPC to by We demonstrated that to and by Ox-PAPC most Ox-PAPC of by the to the in by in to to oxidative of demonstrated the of by oxidative stress. Ox-PAPC electron in and of on the of in to Ox-PAPC electron in the is in to by and of by Ox-PAPC in regulating expression by Ox-PAPC in that and in regulating in of endothelial expression of human heme oxygenase-1 of of heme oxygenase-1 in human is by of in the and and in the of Ox-PAPC to in the of the by Ox-PAPC is in the the of the been Ox-PAPC in and on the of electron NAD(P)H. that Ox-PAPC has a on the to the of electron and the of electron to by the of electron that Ox-PAPC the in the plasma membrane to the of electron the plasma membrane the We that Ox-PAPC of in the plasma membrane in in of endothelial by which membrane and of that the of the membrane membrane in of the of cell and of a of To on the of in membrane on the been that membrane is the of electron transport by in electron transport of electron transport of in and that the is by Ox-PAPC and in the of by Ox-PAPC through of that is of redox status in endothelial and a of in the ecto-NADH oxidase 1 human aortic endothelial cell heme oxygenase-1 oxidoreductase 1 plasma membrane electron transport