TY - JOUR T1 - Iron-induced cardiac damage: role of apoptosis and deferasirox intervention JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.110.172668 SP - jpet.110.172668 AU - Yeling Wang AU - Miaozong Wu AU - Rabaa Al-Rousan AU - Hua Liu AU - Jacqueline Fannin AU - Satyanarayana Paturi AU - Ravi Arvapalli AU - Anjaiah Katta AU - Sunil Kakarla AU - Kevin Rice AU - William E Triest AU - Eric R Blough Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/10/14/jpet.110.172668.abstract N2 - Excess cardiac iron levels are associated with cardiac damage and can result in increased morbidity and mortality. Here we hypothesize that elevations in tissue iron can activate caspase-dependent signaling which lead to increased cardiac apoptosis and fibrosis, and that these alterations can be attenuated by iron chelation. Using iron-overloaded gerbil model, we show that increased cardiac iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the pro-apoptotic regulator Bad (Ser136), and an increased Bax / Bcl-2 ratio. These alterations were coupled with increased activation of the downstream caspase-9 (40/38- and 17-kDa fragments) and apoptosis executioner caspase-3 (19- and 17-kDa fragments), which were accompanied by evidence of elevated cytoskeletal alpha-fodrin cleavage (150- and 120-kDa fragments), discontinuity of myocardial membrane dystrophin immunoreactivity, increases in the number of TUNEL positive cells (nucleic DNA fragmentation) and cardiac fibrosis. Importantly, we demonstrate that administration of deferasirox, a tridentate iron chelator, is associated with diminished tissue iron deposition, attenuated activation of caspases, reduced alpha-fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity and an attenuation of cardiac fibrosis. These results suggest that the activation of caspase-dependent signaling may play a role in the development of iron-induced cardiac apoptosis and fibrosis, and deferasirox, via a reduction in cardiac tissue iron levels, may be useful for decreasing the extent of iron-induced cardiac damage. ER -