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Journal of Lipid Research, Vol. 50, 265-274, February 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

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

Sangderk Lee^*, Rongsong Li^*, Brandon Kim^*, Roland Palvolgyi^*, Tiffany Ho^*, Qian-Zhou Yang^*, Jason Xu^*, Wan Lam Szeto^*, Henry Honda and Judith A. Berliner^1,*,

^* Department of Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, CA 90095
Division of Cardiology, Department of Medicine, University of California-Los Angeles, Los Angeles, CA 90095

^* This study was supported by National Institute of Health (NIH) grants HL30568 and HL064731 (J.A.B.) and postdoctoral fellowship from American Heart Association (S.L.).

Published, JLR Papers in Press, August 29, 2008.

¹ To whom correspondence should be addressed. e-mail: jberliner{at}mednet.ucla.edu

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 PMET complex in HAECs from inside to outside [as determined by extracellular 2-(4-iodophenyl)-3-(44-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium (WST-1) reduction] and from outside to inside of the cell (as determined by intracellular NBT reduction). Chemical inhibitors of PMET system and siRNAs to PMET components (NQO1 and eNOX1) significantly decreased HO-1 induction by Ox-PAPC. We present evidence that Ox-PAPC activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in HAEC plays an important role in the induction of HO-1 and PMET inhibitors blocked Nrf2 activation by Ox-PAPC. We hypothesized that PMET activation by Ox-PAPC causes intracellular NAD(P)H depletion, which leads to the increased oxidative stress and HO-1 induction. Supporting this hypothesis, cotreatment of cells with exogenous NAD(P)H and Ox-PAPC significantly decreased oxidative stress and HO-1 induction by Ox-PAPC. Taken together, we demonstrated that the PMET system in HAEC plays an important role in the regulation of cellular redox status and HO-1 expression by Ox-PAPC.

Supplementary key words oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine • plasma membrane electron transport • Nrf2 • atherosclerosis • endothelium

Abbreviations: DC, dicoumarol; DPI, diphenyleneiodonium; eNOX1, ecto-NADH oxidase 1; HAEC, human aortic endothelial cell; HO-1, heme oxygenase-1; IL-8, interleukin-8; mPMS, 1-methoxy-5-methylphenazinium, methylsulfate; NBT, nitrobluetetrazolium; NQO1, NAD(P)H:quinone oxidoreductase 1; Nrf2, nuclear factor (erythroid-derived 2)-like 2; Ox-PAPC, oxidized-1-palmitoyl-2-arachidonyl-sn-glycerol-3-phosphocholine; PEIPC, 1-palmitoyl-2-(5,6-epoxyisoprostane E2]-sn-glycerol-3-phosphocholine; PGPC, 1-palmitoyl-2-glutaroyl-sn-glycerol-3-phosphocholine; PMET, plasma membrane electron transport; WST-1, 2-(4-iodophenyl)-3-(44-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium

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