Journal
FASEB JOURNAL
Volume 30, Issue 8, Pages 2885-2898Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.201500146R
Keywords
autotaxin; G-protein-coupled receptors; lysophosphatidylcholine; lysophospholipase D; rac
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Funding
- U.S. National Institutes of Health, National Heart, Lung, and Blood Institute [HL-R01-105509, 1F32HL127972]
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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 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-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 mu M; lungs, 20 mM; 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 mu M; lungs, 25 mu M; K-i, 0.34 mu M) or cellular knockdown of LPAR type 1 decreased oxidant generation and blocked translocation of rac1 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.
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