Date of Award

2009

Degree Name

Doctor of Philosophy

College

Joan C. Edwards School of Medicine

Type of Degree

Ph.D.

Document Type

Dissertation

First Advisor

Eric Blough

Second Advisor

Monica Valentovic

Third Advisor

Elsa Mangiarua

Abstract

Iron overload is a significant, world-wide problem that results in several chronic diseases including cardiovascular, hepatic and pancreatic complications.The newly developed, orally effective, iron chelating agent deferasirox is thought to offer tremendous promise as an alternative to deferoxamine. However, the efficacy and safety profile of deferasirox is not yet clear. In the present study, the efficacy of deferasirox in removing iron from target tissues has been examined using the gerbil model of iron overload. Deferasirox administration resulted in a significant reduction of iron from cardiac and hepatic tissue. In addition deferasirox reduced iron induced increase in cardiac and hepatic oxidative stress indices including ferritin expression, superoxide production, protein oxidation, and ERK1/2, P38, and JNK phosphorylation. These results indicate that deferasirox is capable of attenuating iron- induced oxidative stress. Continuing our investigation we observed that iron overload was also associated with an increase in hepatic cell death and upregulation of Bax/Bcl-22, Bad expression, and caspase-3 cleavage. These levels were significantly lower with deferasirox treatment suggesting a protective role against cell death. The primary overall goal of managing iron overload is to reduce/prevent cardiac or other organ complications. In the present study we examined the effect of iron overload on cardiac remodeling and functional parameters, and the effectiveness of chronic deferasirox administration to prevent or reduce these changes using electro- and echocardiographic procedures. Compared to control, iron overload was associated with left ventricular remodeling, arrhythmia, valve regurgitation, and a decline in cardiac function. These changes were highly preserved with deferasirox treatment. Following the preceding studies, we demonstrated a reduction in tissue iron with deferasirox treatment in the iron overloaded gerbil model. The findings of the present report established for the first time that deferasirox treatment is capable of attenuating iron-induced increase in oxidative stress indices, tissue ferritin protein expression, cell death, and more importantly, iron related cardiovascular alterations. These findings suggest that deferasirox may be useful in protection against iron-induced organ damage. The present report also provides data elaborating on the possible mechanism by which iron overload contributes to cellular injury, thereby allowing the development of better therapeutic regimens to control this disorder.

Subject

Deferasirox

Subject

Iron Overload

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