Lysophosphatidic acid induces endothelial cell death by modulating the redox environment.
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 LPA(1) receptor, because the specific LPA(1) 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.
Brault
Sonia
S
Department of Pediatrics, Research Center, Hôpital Sainte-Justine, 3175 Côte Sainte-Catherine, Montréal, Québec, Canada H3T 1C5.
Gobeil
Fernand
F
Fortier
Audrey
A
Honoré
Jean-Claude
JC
Joyal
Jean-Sébastien
JS
Sapieha
Przemyslaw S
PS
Kooli
Amna
A
Martin
Elodie
E
Hardy
Pierre
P
Ribeiro-da-Silva
Alfredo
A
Peri
Krishna
K
Lachapelle
Pierre
P
Varma
Daya
D
Chemtob
Sylvain
S
D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects*; D001921:Brain / Q000098:blood supply / Q000166:cytology; D016923:Cell Death; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000648:ultrastructure; D004730:Endothelium, Vascular / Q000166:cytology; D007700:Kinetics; D008246:Lysophospholipids / Q000494:pharmacology*; D008954:Models, Biological; D010084:Oxidation-Reduction / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D034421:Sus scrofa
D008246:Lysophospholipids; C032881:lysophosphatidic acid