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

Redondo‐Horcajo, Mariano; Romero, Natália; Martínez-Acedo, Pablo; Martínez‐Ruiz, Antonio; Quijano, Celia; Lourenço, Cátia F.; Movilla, Nieves; Enríquez, José Antonio; Rodrı́guez-Pascual, Fernando; Rial, Eduardo; Radí, Rafael; Vázquez, Jesús; Lamas, Santiago

doi:10.1093/cvr/cvq028

Cited by 66 publications

(41 citation statements)

References 50 publications

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“…Hence, even at saturating levels of cGMP for the non-nitrated enzyme, the kinase activity seems to be lower in the nitrated protein. Our findings are also in agreement with other studies that have also shown that the negative charge imparted by nitration alters the hydrogen bonding network between the substrate and protein in such enzymes as manganese superoxide dismutase (46), glutathione reductase (47), and prostacyclin synthase (48). However, it should be noted that our results appear to be contradictory to a previous study.…”

Section: Discussionsupporting

confidence: 87%

Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

Aggarwal

Groß

Rafikov

et al. 2014

Journal of Biological Chemistry

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Background: PKG-1␣ nitration plays an important role in the development of pulmonary hypertension. Results: We identified Tyr 247 as the key residue susceptible to nitration and inhibition of PKG-1␣. Conclusion: Nitration attenuates PKG activity by reducing its affinity for cGMP. Significance: Preventing the nitration of PKG-1␣ could prevent the phenotypic remodeling in the blood vessels during the development of a number of cardiovascular diseases.

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Section: Discussionsupporting

confidence: 87%

Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

Aggarwal

Groß

Rafikov

et al. 2014

Journal of Biological Chemistry

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“…Peroxynitrite is well-established to inactivate MnSOD by nitrating a critical Tyr residue (Tyr 34) at the enzyme active site both in vitro and in vivo (102,137,141,163). A recent study also reported Tyr nitration of MnSOD and resultant inactivation of the enzyme upon exposure to NO (162).…”

Section: Mnsod Regulation Via Other Post-translational Modifications mentioning

confidence: 99%

MnSOD in Oxidative Stress Response-Potential RegulationviaMitochondrial Protein Influx

Candas

2014

Antioxidants & Redox Signaling

274

178

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Significance: The mitochondrial antioxidant manganese superoxide dismutase (MnSOD) is encoded by genomic DNA and its dismutase function is fully activated in the mitochondria to detoxify free radical O 2 -generated by mitochondrial respiration. Accumulating evidence shows an extensive communication between the mitochondria and cytoplasm under oxidative stress. Not only is the MnSOD gene upregulated by oxidative stress, but MnSOD activity can be enhanced via the mitochondrial protein influx (MPI). Recent Advances: A cluster of MPI containing cytoplasmic/nuclear proteins, such as cyclins, cyclin-dependent kinases, and p53 interact with and alter MnSOD activity. These proteins modulate MnSOD superoxide scavenging activity via post-translational modifications in the mitochondria. In addition to well-established pathways in gene expression, recent findings suggest that MnSOD enzymatic activity can also be enhanced by phosphorylation of specific motifs in mitochondria. This review attempts to discuss the pre-and post-translational regulation of MnSOD, and how these modifications alter MnSOD activity, which induces a cell adaptive response to oxidative stress. Critical Issues: MnSOD is biologically significant to aerobic cells. Its role in protecting the cells against the deleterious effects of reactive oxygen species is evident. However, the exact network of MnSOD-associated cellular adaptive reaction to oxidative stress and its post-translational modifications, especially its enzymatic enhancement via phosphorylation, is not yet fully understood. Future Directions: The broad discussion of the multiple aspects of MnSOD regulation, including gene expression, protein modifications, and enzymatic activity, will shed light onto the unknown mechanisms that govern the prosurvival networks involved in cellular and mitochondrial adaptive response to genotoxic environment. Antioxid. Redox Signal. 20, 1599Signal. 20, -1617

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“…Aza increases EC survival, 17 in contrast to sirolimus, which induces apoptosis, causing the thrombotic problems in sirolimus-coated coronary stents, 18 or cyclosporine A that is toxic to ECs and provokes vasculopathy. 19 We and others have previously shown that Aza maintains the contractile phenotype of smooth muscle cells 20,21 and has an anti-inflammatory effect in macrophages 22 and T cells. 23 Thus, Aza seems a good candidate drug to treat inflammation and protect the vessel wall.…”

mentioning

confidence: 92%

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

Marinković

Hibender

Hoogenboezem

et al. 2013

ATVB

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Objective— In aortic aneurysms the arterial vessel wall is dilated because of destruction of its integrity, which may lead to lethal vessel rupture. Chronic infiltration of inflammatory cells into the vessel wall is fundamental to aneurysm pathology. We aim to limit aneurysm growth by inhibition of inflammation and reducing endothelial cell (EC) activation with immunosuppressive drug azathioprine (Aza). Approach and Results— Aza and its metabolite 6-mercaptopurine have anti-inflammatory effects on leukocytes. We here demonstrate that treatment of ECs with 6-mercaptopurine inhibits cell activation as illustrated by reduced expression of interleukin-12, CCL5, CCL2, and vascular cell adhesion molecule-1 and inhibition of monocyte–EC adhesion. The underlying mechanism of 6-mercaptopurine involves suppression of GTPase Rac1 activation, resulting in reduced phosphorylation of c-Jun-terminal-N-kinase and c-Jun. Subsequently, the effect of Aza was investigated in aneurysm formation in the angiotensin II aneurysm mouse model in apolipoprotein E–deficient mice. We demonstrated that Aza decreases de novo aortic aneurysm formation from an average aneurysm severity score of 2.1 (control group) to 0.6 (Aza group), and that Aza effectively delays aorta pathology in a progression experiment, resulting in a reduced severity score from 2.8 to 1.7 in Aza-treated mice. In line with the in vitro observations, Aza-treated mice showed less c-Jun-terminal-N-kinase activation in ECs and reduced leukocyte influx in the aortic wall. Conclusions— The immunosuppressive drug Aza has an anti-inflammatory effect and in ECs inhibits Rac1 and c-Jun-terminal-N-kinase activation, which may explain the protective effect of Aza in aneurysm development and, most importantly for clinical implications, aneurysm severity.

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

Cited by 66 publications

References 50 publications

Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

Nitration of Tyrosine 247 Inhibits Protein Kinase G-1α Activity by Attenuating Cyclic Guanosine Monophosphate Binding

MnSOD in Oxidative Stress Response-Potential RegulationviaMitochondrial Protein Influx

Immunosuppressive Drug Azathioprine Reduces Aneurysm Progression Through Inhibition of Rac1 and c-Jun-Terminal-N-Kinase in Endothelial Cells

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