Reexamining iron’s role in heart disease

Chemically modified forms of the LDL are thought to serve as the direct source of cholesterol in atherosclerotic plaques, but the nature of the chemical modification that converts native LDL to an atherogenic species in vivo is a matter of much debate. LDL can be oxidized in vitro by treatment with iron or other metal ions to generate a form that accumulates in cultured cells, mimicking the genesis of foam cells in the early atherosclerotic lesion. The potential importance of iron in atherogenesis has been suggested frequently, and some epidemiological evidence suggests that high serum iron levels can promote heart disease. Arguing against such an association is the finding that people with the iron-overload disorder hemochromatosis seem to develop arterial lesions more slowly than those in the general population, raising the possibility that high serum iron is somehow protective. Kirk et al. now make a similar observation in a more tractable experimental system. Here, they show that high levels of dietary iron are associated with delayed progression of arterial lesions in atherosclerosis-prone mice. The authors propose no mechanism for this paradoxical effect, although they exclude the possibility that iron overload reduces serum lipoprotein levels or induces a systemic increase in protective antioxidants. It remains possible that iron exerts both pro-and anti-atherogenic roles, but this work raises considerable doubt that the former predominate in the physiological setting.