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

作者：Lee Sangderk; Li Rongsong; Kim Brandon; Palvolgyi Roland; Ho Tiffany; Yang Qian Zhou; Xu Jason; Szeto Wan Lam; Honda Henry; Berliner Judith A^*

来源：The Journal of Lipid Research, 2009, 50(2): 265-274.

DOI：10.1194/jlr.M800317-JLR200

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

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. Lee, S., R. Li, B. Kim, R. Palvolgyi, T. Ho, Q-Z. Yang, J. Xu, W. L. Szeto, H. Honda, and J. A. Berliner. Ox-PAPC activation of PMET system increases expression of heme oxygenase-1 in human aortic endothelial cell. J. Lipid Res. 2009. 50: 265-274.

• 出版日期2009-2