Phospholipase D Signaling Mediates Reactive Oxygen Species-Induced Lung Endothelial Barrier Dysfunction

We have demonstrated that Reactive oxygen species stimulate lung endothelial cell phospholipase D that generates phosphatidic acid, a second messenger involved in signal transduction

Peter V. Usatyuk


Scholarcy highlights

  • Our earlier studies have demonstrated that Reactive oxygen species activate Phospholipase D and modulate the distribution of cytoskeletal and focal adhesion proteins in bovine pulmonary artery endothelial cell
  • The results of this study demonstrated that the PLD‐generated intracellular bioactive lipid signal mediator, phosphatidic acid, was an essential player in the ROS‐induced barrier dysfunction in lung vascular ECs
  • In contrast to PLD activation, increase of albumin clearance in response to H2O2 exposure occurred at later time periods between 60 and 180 minutes of exposure. These results demonstrated that H2O2 mediated PLD activation preceded the barrier dysfunction in BPAECs
  • Role of PLD1 and PLD2 in ROS‐mediated cytoskeletal reorganization and focal adhesion protein redistribution in ECs Our recent study has demonstrated that H2O2 treatment in endothelial cells induces the reorganization of cytoskeleton and focal adhesion proteins and decreases the Transendothelial cell electrical resistance, suggesting that the cytoskeleton and focal adhesion proteins play an important role in the oxidant‐mediated vascular endothelial barrier function that is regulated by the cell‐cell
  • Others and we have demonstrated that exposure of ECs to ROS or edematic agents induce actin stress fibers, affect the focal adhesion and adherens junction proteins and alter the EC
  • Reactive oxygen species‐induced permeability changes in the endothelium are dependent on signaling pathways involving the increase in intracellular calcium, activation of Rho, MLCK, protein kinase C, Akt, mitogen‐activated protein kinases and Src kinases. There is considerable evidence that many of these signaling pathways modulate the cytoskeleton, adherens junction assembly and cell‐extracellular matrix attachments towards regulation of the endothelial cell barrier function. Our current results on PLD1‐and PLD2‐dependent regulation of the ROS‐mediated permeability involving actin stress fiber formation and VE‐cadherin redistribution are in agreement with the involvement of cytoskeleton reorganization and tight junction proteins in LPA/S1P‐induced endothelial permeability. In this study, a selective role of PLD2, but not PLD1, in control of endothelial cells permeability by LPA or S1P involving the stress fiber formation and occludin down‐regulation has been observed in HUVECs. a requirement of Phospholipase D activity for the actin stress fiber formation has been demonstrated in fibroblasts, epithelial cells, and aortic ECs

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