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 pr
esent at vascular sites of inflammation; therefore, we undertook a stu
dy 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 endothelia
l cells (EC) exposed to nitric oxide donors synthesize markedly less f
erritin. Treatment of EC with a nitric oxide donor increases IRP affin
ity 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, thes
e same cells become sensitive to oxidants, whereas iron-treated EC tha
t are ferritin-rich continue to be resistant. In conclusion, NO inhibi
ts the increase of EC ferritin after exposure to iron but provides sho
rt-term protection against oxidants; ferritin, in turn, provides durab
le cytoprotection by inactivating reactive iron.