Nitric oxide donors modulate ferritin and protect endothelium from oxidative injury.
Ferritin protects endothelial cells from the damaging effects of iron-catalyzed oxidative injury. Regulation of ferritin occurs through the formation of an iron-sulfur cluster within a cytoplasmic protein, the iron regulatory protein (IRP) that controls ferritin mRNA translation. Nitric oxide has been shown to inhibit iron-sulfur proteins and is present at vascular sites of inflammation; therefore, we undertook a study to examine the influence of nitric oxide on changes in endothelial cell ferritin content in response to iron exposure, and the subsequent effects on susceptibility to oxidative injury. Iron-loaded endothelial cells (EC) exposed to nitric oxide donors synthesize markedly less ferritin. Treatment of EC with a nitric oxide donor increases IRP affinity for ferritin mRNA concomitant with a loss of cytoplasmic aconitase activity in iron-laden EC. Iron-treated EC exposed to NO donors were resistant to oxidative injury despite their low ferritin content when examined 1 h after the treatment period. In contrast, 24 h later, these same cells become sensitive to oxidants, whereas iron-treated EC that are ferritin-rich continue to be resistant. In conclusion, NO inhibits the increase of EC ferritin after exposure to iron but provides short-term protection against oxidants; ferritin, in turn, provides durable cytoprotection by inactivating reactive iron.
Department of Medicine, Medical College of Wisconsin, Milwaukee, USA. MJUCKETT@HEMONC.MCW.EDU
M B
MB
Juckett
M
M
Weber
J
J
Balla
H S
HS
Jacob
G M
GM
Vercellotti
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001483:Base Sequence; D015152:Blotting, Northern; D002478:Cells, Cultured; D015342:DNA Probes / Q000737:chemistry; D004727:Endothelium / Q000378:metabolism*; D005293:Ferritins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D006427:Hemin / Q000378:metabolism; D006801:Humans; D058085:Iron Compounds / Q000378:metabolism / Q000494:pharmacology; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins / Q000378:metabolism*; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000494:pharmacology*; D018384:Oxidative Stress; D010396:Penicillamine / Q000031:analogs & derivatives / Q000378:metabolism; D011073:Polyamines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D026423:S-Nitroso-N-Acetylpenicillamine; D013552:Swine / Q000378:metabolism; D014471:Umbilical Veins / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology
D015342:DNA Probes; D058085:Iron Compounds; D035925:Iron-Regulatory Proteins; D007506:Iron-Sulfur Proteins; D011073:Polyamines; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014665:Vasodilator Agents; C005391:diethylenetriamine; D009569:Nitric Oxide; D006427:Hemin; D026423:S-Nitroso-N-Acetylpenicillamine; D005293:Ferritins; D006419:Heme Oxygenase (Decyclizing); D000154:Aconitate Hydratase; D010396:Penicillamine