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Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide.
Cardiovasc Res. 2010 Jul 15; 87(2):356-65.CR

Abstract

AIMS

Cyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosuppression 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.

Authors+Show Affiliations

Departamento Medicina Celular y Molecular, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid, Spain.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

20106845

Citation

Redondo-Horcajo, Mariano, et al. "Cyclosporine A-induced Nitration of Tyrosine 34 MnSOD in Endothelial Cells: Role of Mitochondrial Superoxide." Cardiovascular Research, vol. 87, no. 2, 2010, pp. 356-65.
Redondo-Horcajo M, Romero N, Martínez-Acedo P, et al. Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide. Cardiovasc Res. 2010;87(2):356-65.
Redondo-Horcajo, M., Romero, N., Martínez-Acedo, P., Martínez-Ruiz, A., Quijano, C., Lourenço, C. F., Movilla, N., Enríquez, J. A., Rodríguez-Pascual, F., Rial, E., Radi, R., Vázquez, J., & Lamas, S. (2010). Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide. Cardiovascular Research, 87(2), 356-65. https://doi.org/10.1093/cvr/cvq028
Redondo-Horcajo M, et al. Cyclosporine A-induced Nitration of Tyrosine 34 MnSOD in Endothelial Cells: Role of Mitochondrial Superoxide. Cardiovasc Res. 2010 Jul 15;87(2):356-65. PubMed PMID: 20106845.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cyclosporine A-induced nitration of tyrosine 34 MnSOD in endothelial cells: role of mitochondrial superoxide. AU - Redondo-Horcajo,Mariano, AU - Romero,Natalia, AU - Martínez-Acedo,Pablo, AU - Martínez-Ruiz,Antonio, AU - Quijano,Celia, AU - Lourenço,Catia F, AU - Movilla,Nieves, AU - Enríquez,Jose Antonio, AU - Rodríguez-Pascual,Fernando, AU - Rial,Eduardo, AU - Radi,Rafael, AU - Vázquez,Jesús, AU - Lamas,Santiago, Y1 - 2010/01/27/ PY - 2010/1/29/entrez PY - 2010/1/29/pubmed PY - 2010/10/13/medline SP - 356 EP - 65 JF - Cardiovascular research JO - Cardiovasc Res VL - 87 IS - 2 N2 - AIMS: Cyclosporine A (CsA) has represented a fundamental therapeutic weapon in immunosuppression 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. SN - 1755-3245 UR - https://www.unboundmedicine.com/medline/citation/20106845/Cyclosporine_A_induced_nitration_of_tyrosine_34_MnSOD_in_endothelial_cells:_role_of_mitochondrial_superoxide_ L2 - https://academic.oup.com/cardiovascres/article-lookup/doi/10.1093/cvr/cvq028 DB - PRIME DP - Unbound Medicine ER -