Ferritin: A cytoprotective antioxidant strategem of endothelium

G. Balla, H. S. Jacob, J. Balla, M. Rosenberg, K. Nath, F. Apple, J. W. Eaton, G. M. Vercellotti

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Abstract

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.

Original languageEnglish
Pages (from-to)18148-18153
Number of pages6
JournalJournal of Biological Chemistry
Volume267
Issue number25
Publication statusPublished - Jan 1 1992

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Balla, G., Jacob, H. S., Balla, J., Rosenberg, M., Nath, K., Apple, F., Eaton, J. W., & Vercellotti, G. M. (1992). Ferritin: A cytoprotective antioxidant strategem of endothelium. Journal of Biological Chemistry, 267(25), 18148-18153.