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J. Biol. Chem., Vol. 281, Issue 2, 775-781, January 13, 2006

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Hydrolysis of Phosphatidylserine-exposing Red Blood Cells by Secretory Phospholipase A₂ Generates Lysophosphatidic Acid and Results in Vascular Dysfunction^*

Nikole A. Neidlinger1, Sandra K. Larkin, Amrita Bhagat, Gregory P. Victorino, and Frans A. Kuypers

From the Department of Surgery, University of California, San Francisco-East Bay, Oakland, California 94602 and Children's Hospital Oakland Research Institute, Oakland, California 94609

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 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 sPLA₂, at levels of sPLA₂ observed under inflammatory conditions (100 ng/ml) PS-exposing red blood cells hemolyzed and generated LPA (1.2 nM/10⁸ 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 µM LPA, and the combination of PS-exposing red blood cells with PLA₂ 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 µM LPA in vivo were 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.

Received for publication, May 26, 2005 , and in revised form, October 19, 2005.

^* This work was supported in part by National Institutes of Health Grants HL66355 and HL070583 (to F. A. K.) and an American College of Surgeons faculty research grant (to G. .P. V.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Rm. 1114, 5700 Martin Luther King, Jr. Way, Oakland, CA 94609-1673. Tel.: 510-450-7621; Fax: 510-450-7910; E-mail: NeidlingerN{at}surgery.ucsf.edu.

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