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 leads to increased cardiac apoptosis and
fibrosis, and that these alterations can be attenuated by
iron chelation. Using an
iron-overloaded gerbil model, we show that increased cardiac
iron is associated with reduced activation of Akt (Ser473 and Thr308), diminished phosphorylation of the proapoptotic regulator Bad (Ser136), and an increased Bax/Bcl-2 ratio. These
iron-overload-induced alterations in Akt/Bad phosphorylation and Bax/Bcl-2 ratio 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 α-
fodrin cleavage (150- and 120-kDa fragments), discontinuity of myocardial membrane
dystrophin immunoreactivity, increases in the number of
terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells (nucleic DNA fragmentation), and cardiac
fibrosis. We demonstrate that the administration of
deferasirox, a tridentate
iron chelator, is associated with diminished tissue
iron deposition, attenuated activation of
caspases, reduced α-
fodrin cleavage, improved membrane integrity, decreased TUNEL reactivity, and attenuated 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.