Iron overload diminishes atherosclerosis in apoE-deficient mice.
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.
Kirk
E A
EA
Departments of Pathobiology and Nutritional Sciences, University of Washington, Seattle, Washington 98195, USA.
Heinecke
J W
JW
LeBoeuf
R C
RC
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D005260:Female; D054354:Iron Carbonyl Compounds; D019190:Iron Overload / Q000150:complications* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009942:Organometallic Compounds / Q000494:pharmacology; D010084:Oxidation-Reduction; D012333:RNA, Messenger / Q000096:biosynthesis; D014280:Triglycerides / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
D001057:Apolipoproteins E; D009942:Organometallic Compounds; D012333:RNA, Messenger; D014280:Triglycerides; D054354:Iron Carbonyl Compounds; D014443:Tyrosine; C026741:2-tyrosine; D002784:Cholesterol; C007543:dityrosine