The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity

Authors: Petra Kameritsch, Miriam Singer, Christoph Nuernbergk, Natalia Ríos, Aníbal M. Reyes, Kjestine Schmidt, Julian Kirsch, Holger Schneider, Susanna Müller, Kristin Pogoda, Ruicen Cui, Thomas Kirchner, Cor de Wit, Bärbel Lange-Sperandio, Ulrich Pohl, Marcus Conrad, Rafael Radí, Heike Beck - Proceedings of the National Academy of Sciences, PNAS 2021 cited by 63

results in enhanced peroxynitrite steady-state levels in both vascular endothelial cells and vessels by using a highly sensitive redox probe, fluorescein-boronate. High steady-state peroxynitrite levels were further found to coincide with elevated protein tyrosine nitration in renal tissue and a substantial change of the redox state of Prx3 toward the oxidized protein, even though glutaredoxin 2 (Grx2) expression increased in parallel. Additional studies using a mitochondria-specific fluorescence probe (MitoPY1) in vessels revealed that enhanced peroxynitrite levels are indeed generated in mitochondria. Treatment with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin [Mn(III)TMPyP], a peroxynitrite-decomposition catalyst, blunted intravascular formation of peroxynitrite. Our data provide compelling evidence for a yet-unrecognized role of TrxR2 in balancing the nitric oxide/peroxynitrite ratio in endothelial cells in vivo and thus establish a link between enhanced mitochondrial peroxynitrite and disruption of vascular integrity.