Heart protection by ischemic preconditioning: a novel pathway initiated by iron and mediated by ferritin.
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.
Chevion
Mordechai
M
Department of Cellular Biochemistry and Human Genetics, The Hebrew University of Jerusalem, Jerusalem, Israel. chevion@cc.huji.ac.il
Leibowitz
Shirley
S
Aye
Nu Nu
NN
Novogrodsky
Odeya
O
Singer
Adar
A
Avizemer
Oded
O
Bulvik
Baruch
B
Konijn
Abraham M
AM
Berenshtein
Eduard
E
D000818:Animals; D005293:Ferritins / Q000096:biosynthesis*; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000517:prevention & control; D009206:Myocardium / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects
D007502:Iron Chelating Agents; D012333:RNA, Messenger; D005293:Ferritins; D007501:Iron