Iron overload diminishes atherosclerosis in apoE-deficient mice

J Clin Invest. 2001 Jun;107(12):1545-53. doi: 10.1172/JCI7664.

Abstract

It has been proposed that elevated levels of tissue iron increase the risk for atherosclerosis, perhaps by favoring the formation of pro-atherogenic oxidized LDL. Working with apoE-deficient (apoE(-/-)) mice, which do not require a high-fat diet to develop atherosclerosis, we compared the effects of standard diet (0.02% iron) or a 2% carbonyl iron diet. After 24 weeks, mice fed the 2% carbonyl iron diet had twice as much iron in their plasma, a ninefold increase in bleomycin-detectable free iron in their plasma, and ten times as much iron in their livers as control mice. Dietary iron overload caused a modest (30%) rise in plasma triglyceride and cholesterol. Nevertheless, this regimen did not exacerbate, but rather reduced the severity of atherosclerosis by 50%, and it failed to elevate hepatic levels of heme oxygenase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, two markers of metal-catalyzed oxidative damage in vitro, failed to rise in iron-overloaded animals. Our observations suggest that elevated serum and tissue levels of iron are not atherogenic in apoE(-/-) mice. Moreover, they call into question the hypothesis that elevated levels of tissue iron promote LDL oxidation and oxidative stress in vivo.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Apolipoproteins E / genetics*
  • Arteriosclerosis / etiology*
  • Arteriosclerosis / metabolism
  • Arteriosclerosis / pathology
  • Cholesterol / metabolism
  • Female
  • Iron Carbonyl Compounds
  • Iron Overload / complications*
  • Iron Overload / metabolism
  • Liver / metabolism
  • Mice
  • Mice, Knockout
  • Organometallic Compounds / pharmacology
  • Oxidation-Reduction
  • RNA, Messenger / biosynthesis
  • Triglycerides / metabolism
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Apolipoproteins E
  • Organometallic Compounds
  • RNA, Messenger
  • Triglycerides
  • Iron Carbonyl Compounds
  • Tyrosine
  • 2-tyrosine
  • Cholesterol
  • dityrosine