title: Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection.
abstract: 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.
  
  
  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.
authors.affiliation: Medizinische Klinik und Poliklinik I, Munich Heart Alliance, Klinikum Grosshadern of the Ludwig Maximilians-University, Munich, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Horstkotte
authors.forename: Tamara
authors.initials: T
authors.lastname: Perisic
authors.forename: Manuela
authors.initials: M
authors.lastname: Schneider
authors.forename: Philipp
authors.initials: P
authors.lastname: Lange
authors.forename: Melanie
authors.initials: M
authors.lastname: Schroeder
authors.forename: Claudia
authors.initials: C
authors.lastname: Kiermayer
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Tilman
authors.initials: T
authors.lastname: Ziegler
authors.forename: Pankaj K
authors.initials: PK
authors.lastname: Mandal
authors.forename: Robert
authors.initials: R
authors.lastname: David
authors.forename: Sabine
authors.initials: S
authors.lastname: Schulz
authors.forename: Sabine
authors.initials: S
authors.lastname: Schmitt
authors.forename: Julian
authors.initials: J
authors.lastname: Widder
authors.forename: Fred
authors.initials: F
authors.lastname: Sinowatz
authors.forename: Bernhard F
authors.initials: BF
authors.lastname: Becker
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
authors.forename: Michael
authors.initials: M
authors.lastname: Naebauer
authors.forename: Wolfgang M
authors.initials: WM
authors.lastname: Franz
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
authors.forename: Markus
authors.initials: M
authors.lastname: Brielmeier
authors.forename: Hans
authors.initials: H
authors.lastname: Zischka
authors.forename: Marcus
authors.initials: M
authors.lastname: Conrad
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology; D053595:Embryonic Stem Cells / Q000166:cytology; D042783:Endothelial Cells / Q000166:cytology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000201:enzymology*; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000166:cytology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D054481:Thioredoxin Reductase 1 / Q000235:genetics / Q000378:metabolism; D054482:Thioredoxin Reductase 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D013438:Sulfhydryl Compounds; D016572:Cyclosporine; D054481:Thioredoxin Reductase 1; D054482:Thioredoxin Reductase 2; C516125:Txnrd1 protein, mouse; C516128:Txnrd2 protein, mouse; D000111:Acetylcysteine