| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Pediatrics, Pharmacology and Ophthalmology, Research Center of Hospital Ste-Justine, Montreal, Canada; Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
2 Department of Pharmacology, University of Sherbrooke, Sherbrooke, Canada
3 Department of Pediatrics, Pharmacology and Ophthalmology, Research Center of Hospital Ste-Justine, Montreal, Canada
4 Department of Pharmacology & Therapeutics, McGill University, Montreal, Canada
5 Theratechnologies Inc., Montreal, Canada
6 Department of Ophtalmology, McGill University, Montreal, Canada
* To whom correspondence should be addressed. E-mail: sylvain.chemtob{at}umontreal.ca.
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 of human umbilical vein endothelial cells; cell death appeared oncotic rather than apoptotic. LPA-induced cell death was mediated via LPA1 receptor as the specific LPA1 receptor antagonist THG1603 fully abrogated LPA's effects. LPA decreased intracellular GSH levels, and induced a p38 MAPK/JNK-dependent iNOS expression. Pre-treatment with the antioxidant GSH precursor N-acetyl-cysteine (NAC), as well as with inhibitors of NOS (L-NA, 1400W), significantly prevented LPA-induced endothelial cell death (in vitro) to comparable extents; as expected, p38 MAPK (SB203580) and JNK (SP600125) inhibitors also diminished cell death. LPA did not increase indices 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-NA, and combined SB203580 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.
This article has been cited by other articles:
|
|
 |
|
  B. Mayer, A. L. Kleschyov, H. Stessel, M. Russwurm, T. Munzel, D. Koesling, and K. Schmidt Inactivation of Soluble Guanylate Cyclase by Stoichiometric S-Nitrosation Mol. Pharmacol., April 1, 2009; 75(4): 886 - 891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Yang, J. Lafleur, B. R. Mwaikambo, T. Zhu, C. Gagnon, S. Chemtob, A. Di Polo, and P. Hardy The Role of Lysophosphatidic Acid Receptor (LPA1) in the Oxygen-Induced Retinal Ganglion Cell Degeneration Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1290 - 1298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Said, M. J. Socha, J. J. Olearczyk, A. A. Elmarakby, J. D. Imig, and K. Motamed Normalization of the Ovarian Cancer Microenvironment by SPARC Mol. Cancer Res., October 1, 2007; 5(10): 1015 - 1030. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
