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

Proc Natl Acad Sci U S A. 2021 Feb 16;118(7):e1921828118. doi: 10.1073/pnas.1921828118.

Petra Kameritsch ¹, Miriam Singer ¹, Christoph Nuernbergk ¹, Natalia Rios ² ³, Aníbal M Reyes ² ³, Kjestine Schmidt ⁴ ⁵, Julian Kirsch ¹, Holger Schneider ¹, Susanna Müller ⁶, Kristin Pogoda ¹, Ruicen Cui ¹, Thomas Kirchner ⁶, Cor de Wit ⁴ ⁵, Bärbel Lange-Sperandio ⁷, Ulrich Pohl ¹ ⁸, Marcus Conrad ⁹ ¹⁰, Rafael Radi ¹¹ ³, Heike Beck ¹² ⁸

Affiliations

1 Walter Brendel Centre of Experimental Medicine, Biomedical Center Munich, Ludwig-Maximilians-University, 82152 Planegg, Germany.
2 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
3 Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay.
4 Institute of Physiology, University of Lübeck, 23562 Lübeck, Germany.
5 Partner Site Hamburg/Kiel/Lübeck, German Centre for Cardiovascular Research, 23562 Lübeck, Germany.
6 Institute of Pathology, Ludwig Maximilians-University, 80337 Munich, Germany.
7 Department of Pediatrics, Dr. v. Hauner Children's Hospital, Ludwig-Maximilians-University, 80337 Munich, Germany.
8 German Centre for Cardiovascular Research, Munich Heart Alliance, 80802 Munich, Germany.
9 Institute of Metabolism and Cell Death, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
10 Laboratory of Experimental Oncology, National Research Medical University, Moscow 117997, Russia.
11 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, 11800 Montevideo, Uruguay; [email protected] [email protected].
12 Walter Brendel Centre of Experimental Medicine, Biomedical Center Munich, Ludwig-Maximilians-University, 82152 Planegg, Germany; [email protected] [email protected].

PMID: 33579817 DOI: 10.1073/pnas.1921828118

Abstract

The mitochondrial thioredoxin/peroxiredoxin system encompasses NADPH, thioredoxin reductase 2 (TrxR2), thioredoxin 2, and peroxiredoxins 3 and 5 (Prx3 and Prx5) and is crucial to regulate cell redox homeostasis via the efficient catabolism of peroxides (TrxR2 and Trxrd2 refer to the mitochondrial thioredoxin reductase protein and gene, respectively). Here, we report that endothelial TrxR2 controls both the steady-state concentration of peroxynitrite, the product of the reaction of superoxide radical and nitric oxide, and the integrity of the vascular system. Mice with endothelial deletion of the Trxrd2 gene develop increased vascular stiffness and hypertrophy of the vascular wall. Furthermore, they suffer from renal abnormalities, including thickening of the Bowman's capsule, glomerulosclerosis, and functional alterations. Mechanistically, we show that loss of Trxrd2 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.

Keywords

mitochondria; nitric oxide; peroxynitrite; redox; thioredoxin reductase.

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