Title

Deferasirox Removes Cardiac Iron and Attenuates Oxidative Stress in the Iron-overloaded Gerbil

Document Type

Article

Publication Date

9-2009

Abstract

Iron-induced cardiovascular disease is the leading cause of death in iron-overloaded patients. Deferasirox is a novel, once daily oral iron chelator that was recently approved for the treatment of transfusional iron overload. Here, we investigate whether deferasirox is capable of removing cardiac iron and improving iron-induced pathogenesis of the heart using the iron overload gerbil model. Animals were randomly divided into three groups: control, iron overload, and iron overload + deferasirox treatment. Iron-dextran was given 100 mg/kg per 5 days i.p for 10 weeks. Deferasirox treatment was taken post iron loading and was given at 100 mg/kg/day p.o for 1 or 3 months. Cardiac iron concentration was determined by inductively coupled plasma atomic emission spectroscopy. Compared with the untreated group, deferasirox treatment for 1 and 3 months decreased cardiac iron concentration 17.1% (P = 0.159) and 23.5% (P < 0.05), respectively. These treatment-associated reductions in cardiac iron were paralleled by decreases in tissue ferritin expression of 20% and 38% at 1 and 3 months, respectively (P < 0.05). Using oxyblot analysis and hydroethidine fluorescence, we showed that deferasirox significantly reduces cardiac protein oxidation and superoxide abundance by 36 and 47.1%, respectively (P < 0.05). Iron-induced increase in oxidative stress was also associated with increased phosphorylation of ERK-, p38-, and JNK-mitogen-activated protein kinase (MAPK). Interestingly, deferasirox treatment significantly diminished the phosphorylation of all three MAPK subfamilies. These results suggest that deferasirox may confer a cardioprotective effect against iron induced injury.

Comments

This is the final version of the following article: Al-Rousan, R. M., Paturi, S., Laurino, J. P., Kakarla, S. K., Gutta, A. K., Walker, E. M. and Blough, E. R. (2009), Deferasirox removes cardiac iron and attenuates oxidative stress in the iron-overloaded gerbil. Am. J. Hematol., 84: 565–570. doi: 10.1002/ajh.21487, which has been published at http://onlinelibrary.wiley.com/doi/10.1002/ajh.21487/abstract

© 2009 Wiley-Liss, Inc.