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Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection.

AbstractBACKGROUND:
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.
AuthorsJan 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
JournalCirculation (Circulation) Vol. 124 Issue 25 Pg. 2892-902 (Dec 20 2011) ISSN: 1524-4539 [Electronic] United States
PMID22144571 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Enzyme Inhibitors
  • Free Radical Scavengers
  • Sulfhydryl Compounds
  • Cyclosporine
  • Thioredoxin Reductase 1
  • Thioredoxin Reductase 2
  • Txnrd1 protein, mouse
  • Txnrd2 protein, mouse
  • Acetylcysteine
Topics
  • Acetylcysteine (pharmacology)
  • Animals
  • Cell Death (drug effects, physiology)
  • Cells, Cultured
  • Cyclosporine (pharmacology)
  • Embryonic Stem Cells (cytology)
  • Endothelial Cells (cytology)
  • Enzyme Inhibitors (pharmacology)
  • Free Radical Scavengers (pharmacology)
  • Gene Expression Regulation, Enzymologic (physiology)
  • Hematopoietic Stem Cells (cytology)
  • Mice
  • Mice, Knockout
  • Mitochondria (enzymology)
  • Myocardial Reperfusion Injury (drug therapy, metabolism, pathology, physiopathology)
  • Myocytes, Cardiac (cytology)
  • Oxidative Stress (drug effects, physiology)
  • Sulfhydryl Compounds (metabolism)
  • Thioredoxin Reductase 1 (genetics, metabolism)
  • Thioredoxin Reductase 2 (genetics, metabolism)

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