Vascular dysfunction in response to reactive oxygen species (ROS) plays an important role in the development and progression of atherosclerotic lesions. In most cells, mitochondria are the major source of cellular ROS during aerobic respiration. Under most conditions the rates of ROS formation and elimination are balanced through mechanisms that sense relative ROS levels. However, a chronic imbalance in redox homeostasis is believed to contribute to various chronic diseases, including atherosclerosis. Uncoupling protein-2 (UCP2) is a mitochondrial inner membrane protein shown to be a negative regulator of macrophage ROS production. In response to a cholesterolcontaining atherogenic diet, C57BL/6J mice significantly increased expression of UCP2 in the aorta, while mice lacking UCP2, in the absence of any other genetic modification, displayed significant endothelial dysfunction following the atherogenic diet. Compared with wild-type mice, Ucp2 2/2 mice had decreased endothelial nitric oxide synthase, an increase in vascular cell adhesion molecule-1 expression, increased ROS production, and an impaired ability to increase total antioxidant capacity. These changes in Ucp2 2/2 mice were associated with increased aortic macrophage infiltration and more numerous and larger atherosclerotic lesions. These data establish that in the vasculature UCP2 functions as an adaptive antioxidant defense to protect against the development of atherosclerosis in response to a fat and cholesterol diet. Atherosclerosis is a multifactorial chronic vascular disease whose prevalence is increasing worldwide approaching epidemic proportions (1). It is believed that atherosclerosis is initiated by a combination of systemic and local inflammatory events that promote all phases of plaque development and progression (2). Moreover, studies using animal models of atherosclerosis have documented that reactive oxygen species (ROS), which are produced and used by all plaque constituents, serve as one of the drivers of the atherosclerotic process (as reviewed in Refs. 3, 4). Indeed, lesion formation is associated with a collection of events that are regulated by ROS: accumulation of lipid peroxidation products (5, 6), induction of inflammatory/ inflammation-related genes (7), inactivation of nitric oxide (NO) leading to endothelial dysfunction (8, 9), activation of matrix metalloproteinases (10), and increased smooth muscle cell growth (11).As a defense against oxidative stress, most eukaryotic cells are equipped with enzymatic and nonenzymatic mechanisms to neutralize oxidants. These mechanisms have been studied extensively in the heart, and the most important of these include enzymes such as superoxide dismutases (SOD), catalase, and glutathione peroxidase (GPx) (12-15). Under normal conditions, ROS and reactive nitrogen species (RNS) are generated as byproducts of oxidative metabolic activity, but are now appreciated to also serve as signaling molecules in some settings (16)(17)(18)(19). However, under pathophysiological conditions, persis...