Ferritin: a cytoprotective antioxidant strategem of endothelium

• Published in: The Journal of biological chemistry Vol. 267; no. 25; pp. 18148 - 18153
• Main Authors: BALLA, G, JACOB, H. S, BALLA, J, ROSENBERG, M, NATH, K, APPLE, F, EATON, J. W, VERCELLOTTI, G. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Biochemistry and Molecular Biology 05.09.1992
• Subjects: Analytical, structural and metabolic biochemistry; Animals; Antioxidants - metabolism; Aorta; Apoferritins - pharmacology; Arsenic - pharmacology; Arsenites; 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; Lipid Peroxidation; Metalloproteins; Neutrophils - physiology; Other metalloproteins; oxidation; Proteins; Recombinant Proteins - pharmacology; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sodium Compounds; Swine; Ferroprotein; Enzyme; Ferritin; Haem oxygenase (decyclizing); Iron; Antioxidant; Pig; Dose activity relation; Vertebrata; Mammalia; Reaction mechanism; Artiodactyla; Ungulata
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1016/s0021-9258(19)37165-0

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.