Title: The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages.
Authors: Vázquez-Medina, José Pablo; Dodia, Chandra; Weng, Liwei; Mesaros, Clementina; Blair, Ian A; Feinstein, Sheldon I; Chatterjee, Shampa; Fisher, Aron B
Published In FASEB J, (2016 08)
Abstract: Peroxiredoxin 6 (Prdx6) is essential for activation of NADPH oxidase type 2 (NOX2) in pulmonary microvascular endothelial cells (PMVECs), alveolar macrophages (AMs), and polymorphonuclear leukocytes. Angiotensin II and phorbol ester increased superoxide/H2O2 generation in PMVECs, AMs, and isolated lungs from wild-type (WT) mice, but had much less effect on cells or lungs from Prdx6-null or Prdx6-D140A-knock-in mice that lack the phospholipase A2 activity (PLA2) of Prdx6; addition of either lysophosphatidylcholine (LPC) or lysophosphatidic acid (LPA) to cells restored their oxidant generation. The generation of LPC by PMVECs required Prdx6-PLA2 We propose that Prdx6-PLA2 modulates NOX2 activation by generation of LPC that is converted to LPA by the lysophospholipase D activity of autotaxin (ATX/lysoPLD). Inhibition of lysoPLD with HA130 (cells,10 μM; lungs, 20 μM; IC50, 29 nM) decreased agonist-induced oxidant generation. LPA stimulates pathways regulated by small GTPases through binding to G-protein-coupled LPA receptors (LPARs). The LPAR blocker Ki16425 (cells, 10 μM; lungs, 25 μM; Ki, 0.34 μM) or cellular knockdown of LPAR type 1 decreased oxidant generation and blocked translocation of rac1 to plasma membrane. Thus, Prdx6-PLA2 modulates NOX2 activation through generation of LPC for conversion to LPA; binding of LPA to LPAR1 signals rac activation.-Vázquez-Medina, J. P., Dodia, C., Weng, L., Mesaros, C., Blair, I. A., Feinstein, S. I., Chatterjee, S., Fisher, A. B. The phospholipase A2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages.
PubMed ID: 27178323
MeSH Terms: Animals; Cells, Cultured; Endothelial Cells/metabolism*; Endothelium, Vascular/metabolism; Endothelium/metabolism; Gene Knock-In Techniques; Lung/blood supply*; Lung/metabolism; Macrophages, Alveolar/metabolism; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism*; Mice; Mice, Inbred C57BL; Mice, Knockout; NADPH Oxidase 2; NADPH Oxidases/genetics; NADPH Oxidases/metabolism*; Peroxiredoxin VI/genetics; Peroxiredoxin VI/metabolism*; Phospholipases A2/genetics; Phospholipases A2/metabolism*; Receptors, Lysophosphatidic Acid/genetics; Receptors, Lysophosphatidic Acid/metabolism*; Signal Transduction