气候变化领域集成服务门户(CCPortal): The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity

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DOI	10.1073/pnas.1921828118
	The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity
	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.
发表日期	2021
ISSN	00278424
卷号	118 期号:7
英文摘要	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. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Thioredoxin reductase \| nitric oxide \| peroxynitrite \| mitochondria \| redox
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180640
作者单位	Walter Brendel Centre of Experimental Medicine, Biomedical Center Munich, Ludwig-Maximilians-University, Planegg, 82152, Germany; Departamento de Bioquímica, Facultad de Medicina, Universidad de la República, Montevideo, 11800, Uruguay; Centro de Investigaciones Biomédicas, Facultad de Medicina, Universidad de la República, Montevideo, 11800, Uruguay; Institute of Physiology, University of Lübeck, Lübeck, 23562, Germany; Partner Site Hamburg/ Kiel/Lübeck, German Centre for Cardiovascular Research, Lübeck, 23562, Germany; Institute of Pathology, Ludwig Maximilians-University, Munich, 80337, Germany; Department of Pediatrics, Dr. v. Hauner Children’s Hospital, Ludwig-Maximilians-University, Munich, 80337, Germany; German Centre for Cardiovascular Research, Munich Heart Alliance, Munich, 80802, Germany; Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Neuherberg, 85764, Germany; Laboratory of Experimental Oncology, National Research Medical University, Moscow, 117997, Russian Federation
推荐引用方式 GB/T 7714	Kameritsch P.,Singer M.,Nuernbergk C.,et al. The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity[J],2021,118(7).
APA	Kameritsch P..,Singer M..,Nuernbergk C..,Rios N..,Reyes A.M..,...&Beck H..(2021).The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity.Proceedings of the National Academy of Sciences of the United States of America,118(7).
MLA	Kameritsch P.,et al."The mitochondrial thioredoxin reductase system (TrxR2) in vascular endothelium controls peroxynitrite levels and tissue integrity".Proceedings of the National Academy of Sciences of the United States of America 118.7(2021).