Ferritin: a cytoprotective antioxidant strategem of endothelium

J Biol Chem. 1992 Sep 5;267(25):18148-53.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antioxidants / metabolism*
  • Aorta
  • Apoferritins / pharmacology
  • Arsenic / pharmacology
  • Arsenites*
  • Cells, Cultured
  • Cycloheximide / pharmacology
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiology*
  • Ferritins / genetics
  • Ferritins / metabolism*
  • Ferritins / pharmacology*
  • Heme / pharmacology*
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Horses
  • Humans
  • Hydrogen Peroxide / pharmacology
  • Kinetics
  • Lipid Peroxidation*
  • Neutrophils / physiology*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / pharmacology
  • Sodium Compounds*
  • Swine

Substances

  • Antioxidants
  • Arsenites
  • RNA, Messenger
  • Recombinant Proteins
  • Sodium Compounds
  • Heme
  • sodium arsenite
  • Ferritins
  • Apoferritins
  • Cycloheximide
  • Hydrogen Peroxide
  • Heme Oxygenase (Decyclizing)
  • Arsenic