Induction of ferritin synthesis in ischemic-reperfused rat liver: analysis of the molecular mechanisms.
OBJECTIVE
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 perform a cytoprotective action against ROS. The aim of this study was to address the role of ferritin in postischemic reperfusion.


METHODS
Transcriptional and posttranscriptional mechanisms controlling ferritin gene expression were studied in reperfused rat livers.


RESULTS
Proteolysis reduced ferritin levels 2 hours after reperfusion, but a concomitant increase of synthesis, accompanied by enhanced transcription and accumulation of H and L ferritin subunit messenger RNAs (mRNAs), almost re-established normal ferritin content at 4 hours. Pretreatment with interleukin 1 receptor antagonist (IL-1RA) did not prevent the rise of ferritin mRNAs. RNA bandshift assays showed that the activity of the iron regulatory proteins (IRPs), which control ferritin mRNA translation, declined early after reperfusion and recovered progressively thereafter. Pretreatment with either the antioxidant N-acetyl cysteine or IL-1RA 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 ferritin gene transcription, possibly mediated by ferritin-derived iron and ROS-mediated inactivation of IRP, which allows translation of ferritin mRNAs, counteracts this effect and concurs to reestablish the amount of ferritin, which may thus act to limit reperfusion damage.
Tacchini
L
L
Istituto di Patologia Generale, Università di Milano, Italy.
Recalcati
S
S
Bernelli-Zazzera
A
A
Cairo
G
G
D000818:Animals; D004591:Electrophoresis, Polyacrylamide Gel; D005293:Ferritins / Q000096:biosynthesis* / Q000235:genetics; D066298:In Vitro Techniques; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008102:Liver Circulation; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D015424:Reperfusion
D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D017472:Receptors, Interleukin-1; D005293:Ferritins