Iron overload diminishes atherosclerosis in apoE-deficient mice

• Published in: The Journal of clinical investigation Vol. 107; no. 12; pp. 1545 - 1553
• Main Authors: Kirk, E A, Heinecke, J W, LeBoeuf, R C
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01-06-2001
• Subjects: 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
• ISSN: 0021-9738
• DOI: 10.1172/JCI7664

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.