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Mitochondrial Thioredoxin Reductase Is Essential for Early Postischemic Myocardial Protection.
MedLine Citation:
PMID:  22144571     Owner:  NLM     Status:  Publisher    
BACKGROUND: Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury. METHODS AND RESULTS: In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen (Txnrd2-/-ic), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours). Txnrd2-/-ic was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered. CONCLUSIONS: We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.
Jan Horstkotte; Tamara Perisic; Manuela Schneider; Philipp Lange; Melanie Schroeder; Claudia Kiermayer; Rabea Hinkel; Tilman Ziegler; Pankaj K Mandal; Robert David; Sabine Schulz; Sabine Schmitt; Julian Widder; Fred Sinowatz; Bernhard F Becker; Johann Bauersachs; Michael Naebauer; Wolfgang M Franz; Irmela Jeremias; Markus Brielmeier; Hans Zischka; Marcus Conrad; Christian Kupatt
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-5
Journal Detail:
Title:  Circulation     Volume:  -     ISSN:  1524-4539     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-6     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Medizinische Klinik I, Klinikum Großhadern, Department of Veterinary Anatomy II, and Walter Brendel Centre of Experimental Medicine, Ludwig-Maximilians-University, Munich; Institute of Clinical Molecular Biology and Tumor Genetics and Department for Gene Vectors, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich; Department of Comparative Medicine and Institute of Toxicology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg; Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover; DZNE-German Center for Neurodegenerative Diseases, Munich and Helmholtz Zentrum München, Institute of Developmental Genetics, Neuherberg; and Munich Heart Alliance, Munich, Germany.
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