Iron-induced cardiac damage: role of apoptosis and deferasirox intervention.
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.
Wang
Yeling
Y
Center for Diagnostic Nanosystems, Marshall University, 1 John Marshall Drive, Huntington, WV 25755-1090, USA.
Wu
Miaozong
M
Al-Rousan
Rabaa
R
Liu
Hua
H
Fannin
Jacqueline
J
Paturi
Satyanarayana
S
Arvapalli
Ravi Kumar
RK
Katta
Anjaiah
A
Kakarla
Sunil K
SK
Rice
Kevin M
KM
Triest
William E
WE
Blough
Eric R
ER
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D000077588:Deferasirox; D005849:Gerbillinae; D007501:Iron / Q000633:toxicity*; D007502:Iron Chelating Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
D001565:Benzoates; D007502:Iron Chelating Agents; D014230:Triazoles; D007501:Iron; D000077588:Deferasirox