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Kameritsch, P.* ; Singer, M.* ; Nuernbergk, C.* ; Rios, N.* ; Reyes, A.M.* ; Schmidt, K.* ; Kirsch, J.* ; Schneider, H.* ; Müller, S.* ; Pogoda, K.* ; Cui, R.* ; Kirchner, T.* ; de Wit, C.* ; Lange-Sperandio, B.* ; Pohl, U.* ; Conrad, M. ; Radi, R.* ; Beck, H.*

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

Proc. Natl. Acad. Sci. U.S.A. 118:e1921828118 (2021)
Verlagsversion DOI PMC
Free by publisher
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Mitochondria ; Nitric Oxide ; Peroxynitrite ; Redox ; Thioredoxin Reductase; Manganese-superoxide-dismutase; Early Embryonic Lethality; Nitric-oxide; Hydrogen-peroxide; Oxidative Stress; In-vitro; Submitochondrial Particles; Human Peroxiredoxin-5; Nitrosative Stress; Tyrosine Nitration
ISSN (print) / ISBN 0027-8424
e-ISSN 1091-6490
Zeitschrift Proceedings of the National Academy of Sciences of the United States of America
Quellenangaben Band: 118, Heft: 7, Seiten: , Artikelnummer: e1921828118 Supplement: ,
Verlag National Academy of Sciences
Verlagsort 2101 Constitution Ave Nw, Washington, Dc 20418 Usa
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Metabolism and Cell Death (MCD)
Förderungen Universidad de la Republica, Uruguay
Agencia Nacional de Investigacion e Innovacion
Programa de Desarrollo de Ciencias Basicas
Universidad de la Republica (CSIC_Grupos)
Universidad de la Republica (Espacio Interdisciplinario)
Friedrich-Baur Stiftung
Deutsche Forschungsgemeinschaft Priority Programme SPP 1190