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Am J Physiol Regul Integr Comp Physiol 292: R1174-R1183, 2007. First published November 22, 2006; doi:10.1152/ajpregu.00619.2006
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NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Lysophosphatidic acid induces endothelial cell death by modulating the redox environment

Sonia Brault,1,2,* Fernand Gobeil, Jr.,3,* Audrey Fortier,3 Jean-Claude Honoré,1 Jean-Sébastien Joyal,1,2 Przemyslaw S. Sapieha,1 Amna Kooli,1,2 Élodie Martin,1,2 Pierre Hardy,1 Alfredo Ribeiro-da-Silva,2 Krishna Peri,4 Pierre Lachapelle,5 Daya Varma,2 and Sylvain Chemtob1,2

1Departments of Pediatrics, Ophthalmology, and Pharmacology, Research Centre of Hôpital Sainte-Justine, Montreal, Quebec; 2Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec; 3Department of Pharmacology, Université de Sherbrooke, Sherbrooke, Quebec; 4Theratechnologies Inc., Montreal, Quebec; and 5Department of Ophthalmology, McGill University, Montreal Children's Hospital, Montreal, Quebec, Canada

Submitted 30 August 2006 ; accepted in final form 13 November 2006

Oxidant stress plays a significant role in hypoxic-ischemic injury to the susceptible microvascular endothelial cells. During oxidant stress, lysophosphatidic acid (LPA) concentrations increase. We explored whether LPA caused cytotoxicity to neuromicrovascular cells and the potential mechanisms thereof. LPA caused a dose-dependent death of porcine cerebral microvascular as well as human umbilical vein endothelial cells; cell death appeared oncotic rather than apoptotic. LPA-induced cell death was mediated via LPA1 receptor, because the specific LPA1 receptor antagonist THG1603 fully abrogated LPA's effects. LPA decreased intracellular GSH levels and induced a p38 MAPK/JNK-dependent inducible nitric oxide synthase (NOS) expression. Pretreatment with the antioxidant GSH precursor N-acetyl-cysteine (NAC), as well as with inhibitors of NOS [N{omega}-nitro-L-arginine (L-NNA); 1400W], significantly prevented LPA-induced endothelial cell death (in vitro) to comparable extents; as expected, p38 MAPK (SB203580) and JNK (SP-600125) inhibitors also diminished cell death. LPA did not increase indexes of oxidation (isoprostanes, hydroperoxides, and protein nitration) but did augment protein nitrosylation. Endothelial cytotoxicity by LPA in vitro was reproduced ex vivo in brain and in vivo in retina; THG1603, NAC, L-NNA, and combined SB-203580 and SP600125 prevented the microvascular rarefaction. Data implicate novel properties for LPA as a modulator of the cell redox environment, which partakes in endothelial cell death and ensued neuromicrovascular rarefaction.

cerebrovascular hypoxia-ischemia; lipids; nitrosylation


Address for reprint requests and other correspondence: S. Chemtob, Depts. of Pediatrics, Ophthalmology, and Pharmacology, Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec, Canada H3T 1C5 (e-mail: sylvain.chemtob{at}umontreal.ca)




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