Document Detail


Heart protection by ischemic preconditioning: a novel pathway initiated by iron and mediated by ferritin.
MedLine Citation:
PMID:  18817783     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Mordechai Chevion; Shirley Leibowitz; Nu Nu Aye; Odeya Novogrodsky; Adar Singer; Oded Avizemer; Baruch Bulvik; Abraham M Konijn; Eduard Berenshtein
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-09-10
Journal Detail:
Title:  Journal of molecular and cellular cardiology     Volume:  45     ISSN:  1095-8584     ISO Abbreviation:  J. Mol. Cell. Cardiol.     Publication Date:  2008 Dec 
Date Detail:
Created Date:  2008-11-17     Completed Date:  2009-01-22     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0262322     Medline TA:  J Mol Cell Cardiol     Country:  England    
Other Details:
Languages:  eng     Pagination:  839-45     Citation Subset:  IM    
Affiliation:
Department of Cellular Biochemistry and Human Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel. chevion@cc.huji.ac.il
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MeSH Terms
Descriptor/Qualifier:
Animals
Ferritins / biosynthesis*
Iron / antagonists & inhibitors,  metabolism*
Iron Chelating Agents / pharmacology
Ischemic Preconditioning, Myocardial*
Male
Myocardial Contraction / drug effects
Myocardial Reperfusion Injury / metabolism,  prevention & control
Myocardium / metabolism*
Oxidative Stress / drug effects
Protein Biosynthesis* / drug effects
RNA, Messenger / biosynthesis
Rats
Rats, Sprague-Dawley
Signal Transduction* / drug effects
Chemical
Reg. No./Substance:
0/Iron Chelating Agents; 0/RNA, Messenger; 7439-89-6/Iron; 9007-73-2/Ferritins

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