Abstract-Increased oxidative stress in vascular cells plays a key role in the development of endothelial dysfunction and atherosclerosis. Uncoupling protein 2 (UCP2) is an important regulator of intracellular reactive oxygen species (ROS) production. This study was undertaken to test the hypothesis that, UCP2 functions as an inhibitor of the atherosclerotic process in endothelial cells. Adenovirus-mediated UCP2 (Ad-UCP2) overexpression led to a significant increase in endothelial nitric oxide synthase (eNOS) and decrease in endothelin-1 mRNA expression in human aortic endothelial cells (HAECs). Moreover, UCP2 inhibited the increase in ROS production and NF-B activation, and apoptosis of HAECs induced by lysophophatidylcholine (LPC) and linoleic acid. LPC and linoleic acid caused mitochondrial calcium accumulation and transient mitochondrial membrane hyperpolarization, which was followed by depolarization. UCP2 overexpression prevented these processes. In isolated rat aorta, Ad-UCP2 infection markedly improved impaired vascular relaxation induced by LPC. The data collectively suggest that UCP2, functions as a physiologic regulator of ROS generation in endothelial cells. Thus, measures to increase UCP2 expression in vascular endothelial cells may aid in preventing the development and progression of atherosclerosis in patients with metabolic syndrome. etabolic syndrome is a cluster of simultaneously occurring vascular risk factors, such as central obesity, hypertension, dyslipidemia, and glucose intolerance. 1 Impaired endothelium-dependent vascular relaxation (endothelial dysfunction), generally considered a prerequisite for atherosclerosis, is a frequent finding in metabolic syndrome. 2 Subjects with metabolic syndrome frequently display elevated plasma concentrations of free fatty acid (FFA) and oxidized low-density lipoprotein (LDL). 1,[3][4][5] Lipid emulsion and oxidized LDL induce endothelial dysfunction similar to what is observed in metabolic syndrome. 6,7 It is therefore suggested that endothelial dysfunction in metabolic syndrome is mediated, at least in part, by elevated circulating FFA and oxidized LDL levels.Endothelium is important in the regulation of smooth muscle cell growth, migration, and proliferation. In this regard, endothelial apoptosis is an important early event in the pathogenesis of atherosclerosis. 8 Endothelium also modulates vascular tone through the release of relaxing or contracting substances, including nitric oxide (NO), prostacyclin, endothelium-derived hyperpolarizing factor (EDHF), and endothelin-1 (ET-1). Several lines of evidence have suggested that decreased availability of NO or increased availability of ET-1 in the vasculature are central to the pathogenesis of impaired vascular relaxation observed in the early stages of atherosclerosis. 9 -11 Increased oxidative stress in vascular cells is a key mechanism of endothelial dysfunction and atherosclerosis. 12 Various risk factors for atherosclerosis generate intracellular oxidative stress. A relatively high level of oxida...
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