The natural resistance-associated macrophage proteins (Nramps) can modulate inflammatory reactions. Nramps are not only responsible for intracellular divalent metal transport but also determine the macrophage functions in inflammatory processes. In the present study we tested whether Nramp1 is involved in macrophage apoptosis induced by oxidized lipids in atherogenesis. Arterial segments of Watanabe heritable hyperlipidemic rabbits were used for an examination of Nramp1 mRNA by in situ RT-PCR and macrophage immunohistochemistry. Annexin V/PI staining and terminal dUTP nick-end labeling (TUNEL) techniques were used for apoptosis detection. We found that, in macrophage-rich areas (positive to RMA-11) of the rabbit atherosclerotic aorta, there were lesion-dependent increases in Nramp1 mRNA, which are mainly apoptotic foamy macrophages that are positive to TUNEL staining. U937 cells were treated with 7 beta-hydroxycholesterol (7 beta-OH) in the presence or absence of the redox-active iron chelator desferrioxamine (DFO) or 1,10-phenanthroline. The cellular iron chelators considerably reduced, whereas iron compounds enhanced, 7 beta-OH-induced apoptosis and necrosis. DFO also decreased mRNA levels of Nramp1, whereas both iron compounds and 7 beta-OH dramatically enhanced the expression of Nramp1 mRNA, particularly among 7 beta-OH-induced apoptotic cells. We conclude that the enhanced expression of Nramp1 in macrophage regions of atherosclerotic lesions may be associated with ferrous iron-enhanced, oxidized lipid-induced apoptosis. This finding reveals a novel function of Nramp1 in atherogenesis.