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The phospholipase A 2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages
Author(s) -
VázquezMedina José Pablo,
Dodia Chandra,
Weng Liwei,
Mesaros Clementina,
Blair Ian A.,
Feinstein Sheldon I.,
Chatterjee Shampa,
Fisher Aron B.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201500146r
Subject(s) - lysophosphatidic acid , lysophosphatidylcholine , nadph oxidase , chemistry , phospholipase a2 , microbiology and biotechnology , superoxide , receptor , reactive oxygen species , biochemistry , biology , phospholipid , enzyme , membrane , phosphatidylcholine
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/H 2 O 2 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 A 2 activity (PLA 2 ) 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‐PLA 2 . We propose that Prdx6‐PLA 2 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; IC 50 , 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; K i , 0.34 μM) or cellular knockdown of LPAR type 1 decreased oxidant generation and blocked translocation of racl to plasma membrane. Thus, Prdx6‐PLA 2 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 A 2 activity of peroxiredoxin 6 modulates NADPH oxidase 2 activation via lysophosphatidic acid receptor signaling in the pulmonary endothelium and alveolar macrophages. FASEB J. 30, 2885‐2898 (2016). www.fasebj.org