TY - JOUR
T1 - Heart protection by ischemic preconditioning
T2 - A novel pathway initiated by iron and mediated by ferritin
AU - Chevion, Mordechai
AU - Leibowitz, Shirley
AU - Aye, Nu Nu
AU - Novogrodsky, Odeya
AU - Singer, Adar
AU - Avizemer, Oded
AU - Bulvik, Baruch
AU - Konijn, Abraham M.
AU - Berenshtein, Eduard
PY - 2008/12
Y1 - 2008/12
N2 - Ischemic preconditioning is a well-known procedure transiently protecting the heart against injury associated with prolonged ischemia, through mechanism/s only partly understood. The aim of this study was to test whether preconditioning-induced protection of the heart involves an iron-based mechanism, including the generation of an iron signal followed by accumulation of ferritin. In isolated rat hearts perfused in the Langendorff configuration, we measured heart contractility, ferritin levels, ferritin-iron content, and mRNA levels of ferritin subunits. Ischemic preconditioning caused rapid accumulation of ferritin, reaching 359% of the baseline value (set at 100%). This was accompanied by a parallel decline in ferritin-bound iron: from 2191 ± 548 down to 760 ± 34 Fe atoms/ferritin molecule, p < 0.05. Ferritin levels remained high during the subsequent period of prolonged ischemia, and returned to nearly the baseline value during the reperfusion phase. Selective iron chelators (acetyl hydroxamate or Zn-desferrioxamine) abrogated the functional protection and suppressed ferritin accumulation, thus demonstrating the essentiality of an iron signal in the preconditioning-induced protective mechanism. Moreover, introduction of an iron-containing ternary complex, known to import iron into cells, caused a three-fold accumulation of ferritin and simulated the preconditioning-induced functional protection against prolonged myocardial ischemia. The ischemic preconditioning-and-ischemia-induced increase in ferritin levels correlated well with the accumulation of ferritin L-subunit mRNA: 5.44 ± 0.47 vs 1.23 ± 0.15 (units) in the baseline, p < 0.05, suggesting that transcriptional control of ferritin L-subunit synthesis had been activated. Ischemic preconditioning initiates de novo synthesis of ferritin in the heart; the extra ferritin is proposed to serve a 'sink' for redox-active iron, thus protecting the heart from iron-mediated oxidative damage associated with ischemia-reperfusion injury. The present results substantiate a novel iron-based mechanism of ischemic preconditioning and could pave the way for the development of new modalities of heart protection.
AB - Ischemic preconditioning is a well-known procedure transiently protecting the heart against injury associated with prolonged ischemia, through mechanism/s only partly understood. The aim of this study was to test whether preconditioning-induced protection of the heart involves an iron-based mechanism, including the generation of an iron signal followed by accumulation of ferritin. In isolated rat hearts perfused in the Langendorff configuration, we measured heart contractility, ferritin levels, ferritin-iron content, and mRNA levels of ferritin subunits. Ischemic preconditioning caused rapid accumulation of ferritin, reaching 359% of the baseline value (set at 100%). This was accompanied by a parallel decline in ferritin-bound iron: from 2191 ± 548 down to 760 ± 34 Fe atoms/ferritin molecule, p < 0.05. Ferritin levels remained high during the subsequent period of prolonged ischemia, and returned to nearly the baseline value during the reperfusion phase. Selective iron chelators (acetyl hydroxamate or Zn-desferrioxamine) abrogated the functional protection and suppressed ferritin accumulation, thus demonstrating the essentiality of an iron signal in the preconditioning-induced protective mechanism. Moreover, introduction of an iron-containing ternary complex, known to import iron into cells, caused a three-fold accumulation of ferritin and simulated the preconditioning-induced functional protection against prolonged myocardial ischemia. The ischemic preconditioning-and-ischemia-induced increase in ferritin levels correlated well with the accumulation of ferritin L-subunit mRNA: 5.44 ± 0.47 vs 1.23 ± 0.15 (units) in the baseline, p < 0.05, suggesting that transcriptional control of ferritin L-subunit synthesis had been activated. Ischemic preconditioning initiates de novo synthesis of ferritin in the heart; the extra ferritin is proposed to serve a 'sink' for redox-active iron, thus protecting the heart from iron-mediated oxidative damage associated with ischemia-reperfusion injury. The present results substantiate a novel iron-based mechanism of ischemic preconditioning and could pave the way for the development of new modalities of heart protection.
KW - Ferritin
KW - Free radicals
KW - Heart
KW - Iron
KW - Ischemia-reperfusion
KW - Preconditioning
UR - http://www.scopus.com/inward/record.url?scp=55649092852&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2008.08.011
DO - 10.1016/j.yjmcc.2008.08.011
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C2 - 18817783
AN - SCOPUS:55649092852
SN - 0022-2828
VL - 45
SP - 839
EP - 845
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
IS - 6
ER -