Overexpression of thioredoxin-1 in transgenic mice attenuates adriamycin-induced cardiotoxicity

K Shioji, C Kishimoto, H Nakamura, H Masutani… - Circulation, 2002 - Am Heart Assoc
K Shioji, C Kishimoto, H Nakamura, H Masutani, Z Yuan, S Oka, J Yodoi
Circulation, 2002Am Heart Assoc
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 …
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.
Am Heart Assoc