Ox-PAPC activation of plasma membrane electron transport (PMET) system increases expression of heme oxygenase 1 (HO-1) in human aortic endothelial cell (HAEC)

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

Pathology and Laboratory Medicine, University of California-Los Angeles, Los Angeles, CA 90095-1732

Corresponding Author: JBerliner{at}mednet.ucla.edu

Oxidized PAPC (Ox-PAPC) has been demonstrated to accumulate in atherosclerotic lesions and regulates expression of more than 1000 genes in HAEC. Among the most highly induced is heme oxygenase 1 (HO-1), a cell-protective anti-oxidant 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 oxdidase 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 human aortic endothelial cells (HAECs) both from inside to outside (as determined by extracellular 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 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 co-treatment of cells with exogenous NAD(P)H and Ox-PAPC significantly decreased both 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 regulation and HO-1 expression by Ox-PAPC.

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