Reactive oxygen species (ROS) are known to be produced during the development of atherosclerosis, and are thought to play a detrimental role in the progression of the disease, for example through the oxidation of LDL (1). Reactive aldehydes generated through the peroxidation of lipids have also been implicated as agents in the cytotoxic processes that are initiated by ROS. In particular, the reactive aldehydes 4-HNE and acrolein are known to trigger apoptosis, and at high doses necrosis (2). Both acrolein and 4-HNE have been shown to reach high concentrations in and around atherosclerotic plaques, and may be more destructive than the initial production of ROS (3). Several enzyme families are able to detoxify reactive aldehydes, including the aldo-keto reductases (AKR), a superfamily consisting of over 40 NADPH-dependent enzymes that are capable of reducing aldehydes and ketones to alcohols (4). The reduction of 4-HNE and acrolein to the corresponding alcohols is a detoxication step, and may play a role in reducing the damage caused by lipid peroxidation (5). In this study, we have examined the aortic expression of two aldo-keto reductases, AKR1B and AKR1C, in a mouse model of atherosclerosis in order to examine their role in protection against reactive aldehdyes. Apolipoprotein E is essential for maintaining normal cholesterol levels, and ApoE -/- mice that lack this protein are frequently used as a model as they develop early atherosclerotic coronary artery disease. Immunohistochemistry of aortic segments showed increased expression of both AKR enzymes in ApoE -/- mice compared to control C57BL/6 mice. Quantitative Western blot analysis of aortic homogenates indicated over 5-fold increase in expression of AKR1B and AKR1C protein levels. Aortic homogenates from ApoE -/- mice were also shown to have increased ability to metabolise acrolein and 4-HNE compared to control. In an attempt to understand the mechanism responsible for increased expression, cultured C57BL/6 aortic smooth muscle cells were exposed to a sub-lethal concentration of 4-HNE. Western blot analysis revealed increased expression of AKR1B in exposed cells. In addition, pretreated cells expressing increased levels of AKR1B were more resistant to the deleterious effects of 4-HNE. These results indicate that aortic smooth muscle cells display an adaptive response to toxic aldehydes, and suggest that this can provide cytoprotection from toxic insults such as 4-HNE.