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 cel...

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Bibliographic Details
Published in:The Journal of biological chemistry 1992-09, Vol.267 (25), p.18148-18153
Main Authors: BALLA, G, JACOB, HS, BALLA, J, ROSENBERG, M, NATH, K, APPLE, F, EATON, JW, VERCELLOTTI, GM
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Antioxidants - metabolism
Aorta
Apoferritins - pharmacology
Arsenic - pharmacology
Arsenites
Biochemistry & Molecular Biology
Biological and medical sciences
cells
Cells, Cultured
Cycloheximide - pharmacology
damage
endothelium
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - physiology
exposure
ferritin
Ferritins - genetics
Ferritins - metabolism
Ferritins - pharmacology
Fundamental and applied biological sciences. Psychology
heme
Heme - pharmacology
Heme Oxygenase (Decyclizing) - genetics
Heme Oxygenase (Decyclizing) - metabolism
Horses
Humans
Hydrogen Peroxide - pharmacology
Kinetics
Life Sciences & Biomedicine
Lipid Peroxidation
Metalloproteins
Neutrophils - physiology
Other metalloproteins
oxidation
Proteins
Recombinant Proteins - pharmacology
RNA, Messenger - genetics
RNA, Messenger - metabolism
Science & Technology
Sodium Compounds
Swine
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1016/s0021-9258(19)37165-0