Published online before print August 19, 2002, doi: 10.1161/01.CIR.0000027817.55925.B4
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(Circulation. 2002;106:1403.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Overexpression of Thioredoxin-1 in Transgenic Mice Attenuates Adriamycin-Induced Cardiotoxicity
From the Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University (K.S., C.K., Y.Z.); Department of Biological Responses, Institute for Virus Research, Kyoto University (H.N., H.M., S.O., J.Y.); and BioMedical Special Research Unit, Human Stress Research Center, National Institute of Advanced Industrial Science and Technology (H.M., J.Y.), Ikeda/Osaka, Japan.
Correspondence to Chiharu Kishimoto, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, 54 Kawaracho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail kkishi@ kuhp.kyoto-u.ac.jp
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.
Methods and 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.
Key Words: antioxidants • free radicals • cardiomyopathy
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