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Hydrolysis of phosphatidylserine-exposing red blood cells by secretory phospholipase A2 generates lysophosphatidic acid and results in vascular dysfunction.

Abstract
Secretory phospholipase A(2) (sPLA(2)) type IIa, elevated in inflammation, breaks down membrane phospholipids and generates arachidonic acid. We hypothesized that sPLA(2) will hydrolyze red blood cells that expose phosphatidylserine (PS) and generate lysophosphatidic acid (LPA) from phosphatidic acid that is elevated in PS-exposing red blood cells. In turn, LPA, a powerful lipid mediator, could affect vascular endothelial cell function. Although normal red blood cells were not affected by sPLA(2), at levels of sPLA(2) observed under inflammatory conditions (100 ng/ml) PS-exposing red blood cells hemolyzed and generated LPA (1.2 nM/10(8) RBC). When endothelial cell monolayers were incubated in vitro with LPA, a loss of confluence was noted. Moreover, a dose-dependent increase in hydraulic conductivity was identified in rat mesenteric venules in vivo with 5 microM LPA, and the combination of PS-exposing red blood cells with PLA(2) caused a similar increase in permeability. In the presence of N-palmitoyl L-serine phosphoric acid, a competitive inhibitor for the endothelial LPA receptor, loss of confluence in vitro and the hydraulic permeability caused by 5 microM LPA in vivo were abolished. The present study demonstrates that increased sPLA(2) activity in inflammation in the presence of cells that have lost their membrane phospholipid asymmetry can lead to LPA-mediated endothelial dysfunction and loss of vascular integrity.
AuthorsNikole A Neidlinger, Sandra K Larkin, Amrita Bhagat, Gregory P Victorino, Frans A Kuypers
JournalThe Journal of biological chemistry (J Biol Chem) Vol. 281 Issue 2 Pg. 775-81 (Jan 13 2006) ISSN: 0021-9258 [Print] United States
PMID16278219 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Lipids
  • Lysophospholipids
  • N-palmitoylserine phosphoric acid
  • Palmitates
  • Phosphatidic Acids
  • Phosphatidylserines
  • Phosphoserine
  • Phospholipases A
  • Group II Phospholipases A2
  • Phospholipases A2
  • lysophosphatidic acid
Topics
  • Animals
  • Cell Line
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Endothelium, Vascular (cytology, metabolism)
  • Erythrocytes (cytology, metabolism)
  • Group II Phospholipases A2
  • Hemolysis
  • Humans
  • Hydrolysis
  • Inflammation
  • Lipids (chemistry)
  • Lysophospholipids (chemistry)
  • Palmitates (pharmacology)
  • Phosphatidic Acids (chemistry)
  • Phosphatidylserines (chemistry)
  • Phospholipases A (metabolism, physiology)
  • Phospholipases A2
  • Phosphoserine (analogs & derivatives, pharmacology)
  • Rats
  • Time Factors
  • Umbilical Veins (cytology)

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