title: Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity.
abstract: BACKGROUND
  Adriamycin (ADR) is an anticancer drug known to cause severe cardiac toxicity by generating free radicals. We investigated the role of a redox-regulating molecule, thioredoxin-1 (TRX1), in ADR-induced cardiotoxicity.
  
  
  RESULTS
  The in vitro study showed that TRX1 was dose-dependently increased concomitant with the formation of hydroxyl radicals in ADR-treated neonatal rat cardiomyocytes. Lactate dehydrogenase-releasing assay showed that treatment with recombinant human TRX1 suppressed cardiomyocyte injury in ADR-treated cardiomyocytes. To examine the biological significance of TRX1 in vivo, we used transgenic mice expressing increased levels of human TRX1 (TRX1-TG mice). Electron microscopy revealed that mitochondria, myofibrils, and other cellular details were much better maintained in ADR-treated TRX1-TG mice than in ADR-treated nontransgenic (WT) mice. The increase in the protein carbonyl content, a marker of cellular protein oxidation, was suppressed in ADR-treated TRX1-TG mice compared with ADR-treated WT mice. The formation of hydroxyl radicals in ADR-treated heart homogenates of TRX1-TG mice was decreased compared with WT mice. For the survival study, all WT mice treated with ADR died within 6 weeks, but 5 of 6 TRX1-TG mice treated with ADR survived >8 weeks.
  
  
  CONCLUSIONS
  TRX1 is upregulated by intracellular oxidative stress generated by ADR. TRX1 has a protective role against ADR-induced cardiotoxicity by reducing oxidative stress.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Shioji
authors.forename: Chiharu
authors.initials: C
authors.lastname: Kishimoto
authors.forename: Hajime
authors.initials: H
authors.lastname: Nakamura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masutani
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Yuan
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Oka
authors.forename: Junji
authors.initials: J
authors.lastname: Yodoi
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000970:Antineoplastic Agents / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D002316:Cardiotonic Agents / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000633:toxicity*; D017665:Hydroxyl Radical / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D017382:Reactive Oxygen Species / Q000378:metabolism; D016019:Survival Analysis; D013879:Thioredoxins / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D002316:Cardiotonic Agents; D008565:Membrane Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; C491200:Txndc2 protein, mouse; D017665:Hydroxyl Radical; D013879:Thioredoxins; D004317:Doxorubicin