Foam cell death induced by 7beta-hydroxycholesterol is mediated by labile iron-driven oxidative injury: mechanisms underlying induction of ferritin in human atheroma.

Abstract

Human atherosclerotic lesions typically contain large amounts of ferritin associated with apoptotic macrophages and foam cells, although the reasons are unknown. In the present investigation, we studied the relationship between ferritin induction and occurrence of apoptosis in 7beta-hydroxycholesterol (7beta-OH)-treated monocytic cells and macrophages. We found that 7beta-OH enlarges the intracellular labile iron pool, increases formation of reactive oxygen species (ROS), and induces ferritin and cytosolic accumulation of lipid droplets, lysosomal destabilization, and apoptototic macrophage death. Since ferritin is a phase II-type protective protein, our findings suggest that ferritin upregulation here worked as an inefficient defense mechanism. Addition to the culture medium of both a membrane-permeable iron chelator 10-phenanthroline and the non-membrane-permeable iron chelators apoferritin and desferrioxamine afforded significant protection against the 7beta-OH-induced effects. Consequently, endocytosed iron compounds dramatically augmented 7beta-OH-induced cytotoxicity. We conclude that oxidized lipid 7beta-OH causes not only foam cell formation but also oxidative damage with abnormal metabolism of cellular iron. The findings suggest that modulation of iron metabolism in human atheroma may be a potential therapeutic strategy against atherosclerosis.

• Authors: Wei Li, Anna Hellsten, Li-Hua Xu, Da-Ming Zhuang, Katarina Jansson, Ulf T Brunk, Xi-Ming Yuan
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 39 Issue 7 Pg. 864-75 (Oct 01 2005) ISSN: 0891-5849 [Print] United States
• PMID: 16140207 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hydroxycholesterols
• Iron Chelating Agents
• Reactive Oxygen Species
• cholest-5-en-3 beta,7 alpha-diol
• Ferritins
• Iron
• Deferoxamine

Topics

• Animals
• Apoptosis (drug effects)
• Atherosclerosis (physiopathology)
• Deferoxamine (pharmacology)
• Ferritins (biosynthesis)
• Foam Cells (drug effects, pathology)
• Humans
• Hydroxycholesterols (pharmacology)
• Iron (blood)
• Iron Chelating Agents (pharmacology)
• Macrophages (physiology)
• Mice
• Monocytes (drug effects)
• Reactive Oxygen Species (metabolism)
• U937 Cells
• Up-Regulation