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 o xidized LDL. Working with apoE-deficient (apoE(-/-)) mice, which do not req uire 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, mic e fed the 2% carbonyl iron diet had twice as much iron in their plasma, a n inefold 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. Neverthe less, this regimen did not exacerbate, but rather reduced the severity of a therosclerosis by 50%, and it failed to elevate hepatic levels of heme oxyg enase mRNA, which is induced by many different oxidative insults in vitro. Moreover, hepatic levels of protein-bound dityrosine and ortho-tyrosine, tw o markers of metal-catalyzed oxidative damage in vitro, failed to rise in i ron-overloaded animals. Our observations suggest that elevated serum and ti ssue levels of iron are not atherogenic in apoE(-/-) mice. Moreover, they c all into question the hypothesis that elevated levels of tissue iron promot e LDL oxidation and oxidative stress in vivo.