PMID- 20947636
OWN - NLM
STAT- MEDLINE
DCOM- 20110118
LR  - 20181201
IS  - 1521-0103 (Electronic)
IS  - 0022-3565 (Linking)
VI  - 336
IP  - 1
DP  - 2011 Jan
TI  - Iron-induced cardiac damage: role of apoptosis and deferasirox intervention.
PG  - 56-63
LID - 10.1124/jpet.110.172668 [doi]
AB  - 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 alpha-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 alpha-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.
FAU - Wang, Yeling
AU  - Wang Y
AD  - Center for Diagnostic Nanosystems, Marshall University, 1 John Marshall Drive, 
      Huntington, WV 25755-1090, USA.
FAU - Wu, Miaozong
AU  - Wu M
FAU - Al-Rousan, Rabaa
AU  - Al-Rousan R
FAU - Liu, Hua
AU  - Liu H
FAU - Fannin, Jacqueline
AU  - Fannin J
FAU - Paturi, Satyanarayana
AU  - Paturi S
FAU - Arvapalli, Ravi Kumar
AU  - Arvapalli RK
FAU - Katta, Anjaiah
AU  - Katta A
FAU - Kakarla, Sunil K
AU  - Kakarla SK
FAU - Rice, Kevin M
AU  - Rice KM
FAU - Triest, William E
AU  - Triest WE
FAU - Blough, Eric R
AU  - Blough ER
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101014
PL  - United States
TA  - J Pharmacol Exp Ther
JT  - The Journal of pharmacology and experimental therapeutics
JID - 0376362
RN  - 0 (Benzoates)
RN  - 0 (Iron Chelating Agents)
RN  - 0 (Triazoles)
RN  - E1UOL152H7 (Iron)
RN  - V8G4MOF2V9 (Deferasirox)
SB  - IM
MH  - Animals
MH  - Apoptosis/*drug effects/physiology
MH  - Benzoates/pharmacology/*therapeutic use
MH  - Deferasirox
MH  - Gerbillinae
MH  - Iron/*toxicity
MH  - Iron Chelating Agents/pharmacology/*therapeutic use
MH  - Iron Overload/metabolism/*pathology/*prevention & control
MH  - Male
MH  - Myocardium/metabolism/*pathology
MH  - Triazoles/pharmacology/*therapeutic use
EDAT- 2010/10/16 06:00
MHDA- 2011/01/19 06:00
CRDT- 2010/10/16 06:00
PHST- 2010/10/16 06:00 [entrez]
PHST- 2010/10/16 06:00 [pubmed]
PHST- 2011/01/19 06:00 [medline]
AID - jpet.110.172668 [pii]
AID - 10.1124/jpet.110.172668 [doi]
PST - ppublish
SO  - J Pharmacol Exp Ther. 2011 Jan;336(1):56-63. doi: 10.1124/jpet.110.172668. Epub 
      2010 Oct 14.