Ferritin: a cytoprotective antioxidant strategem of endothelium.
Phagocyte-mediated oxidant damage to vascular endothelium is likely involved in various vasculopathies including atherosclerosis and pulmonary leak syndromes such as adult respiratory distress syndrome. We have shown that heme, a hydrophobic iron chelate, is rapidly incorporated into endothelial cells where, after as little as 1 h, it markedly aggravates cytotoxicity engendered by polymorphonuclear leukocyte oxidants or hydrogen peroxide (H2O2). In contrast, however, if cultured endothelial cells are briefly pulsed with heme and then allowed to incubate for a prolonged period (16 h), the cells become highly resistant to oxidant-mediated injury and to the accumulation of endothelial lipid peroxidation products. This protection is associated with the induction within 4 h of mRNAs for both heme oxygenase and ferritin. After 16 h heme oxygenase and ferritin have increased approximately 50-fold and 10-fold, respectively. Differential induction of these proteins determined that ferritin is probably the ultimate cytoprotectant. Ferritin inhibits oxidant-mediated cytolysis in direct relation to its intracellular concentration. Apoferritin, when added to cultured endothelial cells, is taken up in a dose-responsive manner and appears as cytoplasmic granules by immunofluorescence; in a similar dose-responsive manner, added apoferritin protects endothelial cells from oxidant-mediated cytolysis. Conversely, a site-directed mutant of ferritin (heavy chain Glu62----Lys; His65----Gly) which lacks ferroxidase activity and is deficient in iron sequestering capacity, is completely ineffectual as a cytoprotectant. We conclude that endothelium and perhaps other cell types may be protected from oxidant damage through the iron sequestrant, ferritin.
Balla
G
G
Department of Medicine, University of Minnesota, Minneapolis 55455.
Jacob
H S
HS
Balla
J
J
Rosenberg
M
M
Nath
K
K
Apple
F
F
Eaton
J W
JW
Vercellotti
G M
GM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001011:Aorta; D001052:Apoferritins / Q000494:pharmacology; D001151:Arsenic / Q000494:pharmacology; D018053:Arsenites; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D005293:Ferritins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D006418:Heme / Q000494:pharmacology*; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics / Q000378:metabolism*; D006736:Horses; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007700:Kinetics; D015227:Lipid Peroxidation; D009504:Neutrophils / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D017670:Sodium Compounds; D013552:Swine
D000975:Antioxidants; D018053:Arsenites; D012333:RNA, Messenger; D011994:Recombinant Proteins; D017670:Sodium Compounds; D006418:Heme; C017947:sodium arsenite; D005293:Ferritins; D001052:Apoferritins; D003513:Cycloheximide; D006861:Hydrogen Peroxide; D006419:Heme Oxygenase (Decyclizing); D001151:Arsenic