Heart protection by ischemic preconditioning: A novel pathway initiated by iron and mediated by ferritin

Mordechai Chevion*, Shirley Leibowitz, Nu Nu Aye, Odeya Novogrodsky, Adar Singer, Oded Avizemer, Baruch Bulvik, Abraham M. Konijn, Eduard Berenshtein

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)839-845
Number of pages7
JournalJournal of Molecular and Cellular Cardiology
Volume45
Issue number6
DOIs
StatePublished - Dec 2008

Keywords

  • Ferritin
  • Free radicals
  • Heart
  • Iron
  • Ischemia-reperfusion
  • Preconditioning

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