Abstract
The phospholipase A2 (PLA2) activity of peroxiredoxin 6 (Prdx6) is required for NADPH oxidase 2 (Nox2) activation in pulmonary microvascular endothelial cells (PMVEC; JBC 286:1196, 2011). Lysophosphatidylcholine is a major product of the PLA2 activity of Prdx6 that is readily metabolized to lysophosphatidic acid (LPA). LPA is a bioactive lipid that signals through distinct G protein‐coupled receptors (LPA receptors 1‐5). LPA receptor activation results in the stimulation of signaling pathways regulated by small GTPases, such as the Nox2 cytosolic activator Rac1. We propose that LPA receptor signaling activates Nox2 by stimulating Rac1 in PMVEC. Treatment with Ki16425, a selective antagonist of the LPA receptors 1/3, decreased Rac1 translocation to the plasma membrane during phorbol 12‐myristate 13‐acetate (PMA) stimulation in PMVEC; as demonstrated by in situ proximity ligation assays (Duolink®) and western blotting of isolated plasma membrane proteins. In the same way, LPA receptor blockade decreased superoxide and hydrogen peroxide production in response to PMA stimulation. These results suggest that LPA signaling is required for Nox2 activation during agonist stimulation in PMVEC and that Rac1 is a main target of LPA receptor signaling during this process.Grant Funding Source: Supported by HL105509
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