INDUCTION OF FERRITIN SYNTHESIS IN ISCHEMIC-REPERFUSED RAT-LIVER - ANALYSIS OF THE MOLECULAR MECHANISMS

Background & Aims: Iron may catalyze the production of reactive oxygen species (ROS) during postischemic reoxygenation. Ferritin, a cellular iron storage protein, can either represent a source of iron or perfor m a cytoprotective action against ROS. The aim of this study was to ad dress the role of ferritin in postischemic reperfusion. Methods: Trans criptional and posttranscriptional mechanisms controlling ferritin gen e expression were studied in reperfused rat livers. Results: Proteolys is reduced ferritin levels 2 hours after reperfusion, but a concomitan t increase of synthesis, accompanied by enhanced transcription and acc umulation of H and L ferritin subunit messenger RNAs (mRNAs), almost r eestablished normal ferritin content at 4 hours. Pretreatment with int erleukin 1 receptor antagonist (IL-1RA) did not prevent the rise of fe rritin mRNAs. RNA bandshift assays showed that the activity of the iro n regulatory proteins (IRPs), which control ferritin mRNA translation, declined early after reperfusion and recovered progressively thereaft er. Pretreatment with either the antioxidant N-acetyl cysteine or IL-1 RA was sufficient to prevent almost completely down-regulation of IRP activity. Conclusions: Postischemic reperfusion causes degradation of ferritin, possibly increasing iron levels. However, induction of ferri tin gene transcription, possibly mediated by ferritin-devived iron and ROS-mediated inactivation of IRP, which allows translation of ferriti n mRNAs, counteracts this effect and concurs to reestablish the amount of ferritin, which may thus act to limit reperfusion damage.