English   español  
Please use this identifier to cite or link to this item: http://hdl.handle.net/10261/66166
Share/Impact:
Statistics
logo share SHARE logo core CORE   Add this article to your Mendeley library MendeleyBASE

Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL
Exportar a otros formatos:
Title

Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide

AuthorsRedondo-Horcajo, Mariano ; Romero, Natalia; Martínez-Acedo, Pablo ; Martínez-Ruiz, Antonio ; Quijano, Celia; Lourenço, Catia F.; Movilla, Nieves; Enríquez, José Antonio; Rodríguez-Pascual, Fernando ; Rial, Eduardo ; Radi, Rafael; Vázquez, Jesús ; Lamas Peláez, Santiago
KeywordsPeroxynitrite
Calcineurin inhibitors
Reactive nitrogen species
Vascular toxicity
Nitroxidative stress
Issue Date15-Jul-2010
PublisherOxford University Press
CitationCardiovascular Research 87(2):356-365(2010)
AbstractAims Cyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosupression for the past three decades. However, its clinical use is not devoid of side effects, among which hypertension and vascular injury represent a major drawback. Endothelial cells are able to generate reactive oxygen and nitrogen species upon exposure to CsA, including formation of peroxynitrite. This may result in endothelial cell toxicity and increased tyrosine nitration. We have now studied the subcellular origin of superoxide formation in endothelial cells treated with CsA and the biochemical consequences for the function of mitochondrial enzymes. Methods and results By using electron spin resonance and endothelial cells lacking functional mitochondria, we showed that superoxide anion is generated in mitochondria. This was associated with an effect of CsA on bioenergetic parameters: increased mitochondrial membrane potential and inhibition of cellular respiration. In addition, CsA inhibited the activity of the mitochondrial enzymes aconitase and manganese superoxide dismutase (MnSOD). The use of murine lung endothelial cells deficient in endothelial nitric oxide synthase (eNOS) and NOS/peroxynitrite inhibitors allowed us to establish that the presence of eNOS and concomitant NO synthesis and peroxynitrite formation were essential for CsA induced nitration and inhibition of MnSOD activity. As the latter has been shown to become inactivated by nitration, we sought to identify this modification by mass spectrometry analysis. We found that CsA induced specific MnSOD tyrosine 34 nitration both in the recombinant protein and in endothelial cells overexpressing MnSOD.
Conclusion We propose that CsA induced endothelial damage may be related to increased mitochondrial superoxide formation and subsequent peroxynitrite-dependent nitroxidative damage, specifically targeting MnSOD. The inactivation of this key antioxidant enzyme by tyrosine nitration represents a pathophysiological cellular mechanism contributing to self-perpetuation and amplification of CsA-related vascular toxicity
Description10 páginas, 5 figuras -- PAGS nros. 356-365
Publisher version (URL)http://dx.doi.org/10.1093/cvr/cvq028
URIhttp://hdl.handle.net/10261/66166
DOI10.1093/cvr/cvq028
ISSN0008-6363
E-ISSN1755-3245
Appears in Collections:(CIB) Artículos
Files in This Item:
There are no files associated with this item.
Show full item record
 

Related articles:


WARNING: Items in Digital.CSIC are protected by copyright, with all rights reserved, unless otherwise indicated.