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

doi:10.1074/jbc.M505790200

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Papers In Press, published online ahead of print November 8, 2005
J. Biol. Chem, 10.1074/jbc.M505790200
Submitted on May 26, 2005
Accepted on November 8, 2005

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

Nikole A. Neidlinger, Sandra K. Larkin, Amrita Bhagat, Gregory P. Victorino, and Frans A. Kuypers

Kuypers' Lab, Children's Hospital Oakland Research Institute, Oakland, CA 94609-1673

Corresponding Author: NeidlingerN{at}surgery.ucsf.edu

Secretory phospholipase A₂ (sPLA₂) type IIa, elevated in inflammation, breaks down membrane phospholipids and generates arachidonic acid. We hypothesized that sPLA₂ will hydrolyze red blood cells that expose phosphatidylserine (PS), and generate lysophosphatidic acid (LPA), from phosphatidic acid (PA) which is elevated in PS exposing RBC. In turn, LPA, a powerful lipid mediator, could affect vascular endothelial cell function. While normal red blood cells were not affected by sPLA₂, at levels of sPLA₂ observed under inflammatory conditions (100ng/ml), PS-exposing red blood cells hemolyzed and generated LPA (1.2nmol/ 10⁸ RBC). When endothelial cell monolayers were incubated in vitro with PS exposing red blood cells and/or LPA, a loss of confluence was noted. Moreover, a dose-dependent increase in hydraulic conductivity was identified in rat mesenteric venules in vivo with 5µM LPA, and the combination of PS-exposing RBC with sPLA₂ caused 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 5µM LPA in vivo was abolished. The present study demonstrates that increased sPLA₂ 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.

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