Deferasirox removes cardiac iron and attenuates oxidative stress in the iron-overloaded gerbil.
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.
Al-Rousan
Rabaa M
RM
Department of Pharmacology, Physiology, and Toxicology, Marshall University, Huntington, West Virginia 25755-1090, USA.
Paturi
Satyanarayana
S
Laurino
Joseph P
JP
Kakarla
Sunil K
SK
Gutta
Anil K
AK
Walker
Ernest M
EM
Blough
Eric R
ER
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology*; D002316:Cardiotonic Agents; D000077588:Deferasirox; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005849:Gerbillinae; D006321:Heart / Q000187:drug effects; D007501:Iron / Q000032:analysis*; D007502:Iron Chelating Agents / Q000008:administration & dosage / Q000494:pharmacology; D019190:Iron Overload / Q000188:drug therapy*; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001565:Benzoates; D002316:Cardiotonic Agents; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D000077588:Deferasirox