Background-Several clinical studies of statin therapy have demonstrated that lowering low-density lipoprotein (LDL) cholesterol prevents atherosclerotic progression and decreases cardiovascular mortality. In addition, oxidized LDL (oxLDL) is suggested to play roles in the formation and progression of atherosclerosis. However, whether lowering oxLDL alone, rather than total LDL, affects atherogenesis remains unclear. Methods and Results-To clarify the atherogenic impact of oxLDL, lectin-like oxLDL receptor 1 (LOX-1), an oxLDL receptor, was expressed ectopically in the liver with adenovirus administration in apolipoprotein E-deficient mice at 46 weeks of age. Hepatic LOX-1 expression enhanced hepatic oxLDL uptake, indicating functional expression of LOX-1 in the liver. Although plasma total cholesterol, triglyceride, and LDL cholesterol levels were unaffected, plasma oxLDL was markedly and transiently decreased in LOX-1 mice. In controls, atherosclerotic lesions, detected by Oil Red O staining, were markedly increased (by 38%) during the 4-week period after adenoviral administration. In contrast, atherosclerotic progression was almost completely inhibited by hepatic LOX-1 expression. In addition, plasma monocyte chemotactic protein-1 and lipid peroxide levels were decreased, whereas adiponectin was increased, suggesting decreased systemic oxidative stress. Thus, LOX1 expressed in the livers of apolipoprotein E-deficient mice transiently removes oxLDL from circulating blood and possibly decreases systemic oxidative stress, resulting in complete prevention of atherosclerotic progression despite the persistence of severe LDL hypercholesterolemia and hypertriglyceridemia. Conclusions-OxLDL has a major atherogenic impact, and oxLDL removal is a promising therapeutic strategy against atherosclerosis.
Clinical Perspective p 83Oxidative stress might play critical roles in many diseases. In particular, oxidation of LDL might be a key step in the development of atherosclerosis. 4 -6 Oxidized LDL (oxLDL) has been proposed to be involved in many atherogenic changes in the vascular wall such as expression of adhesion molecules, migration of macrophages and smooth muscle cells, release of chemokines, 7 and impairment of endothelial nitric oxide production. 8 Importantly, oxLDL is incorporated into macrophages via receptor-mediated endocytosis, leading to macrophage transformation into foam cells and thus the plaque formation of atherosclerotic lesions. Furthermore, oxLDL itself reportedly induces oxidative stress in endothelial cells, smooth muscle cells, and macrophages, resulting in a vicious cycle of atherogenic plaque formation. 9 the effectiveness of antioxidant therapy against atherosclerosis is controversial. 10 -15 In addition, antioxidants may inhibit not only oxLDL formation but also many other oxidationsensitive pathways. Therefore, it is unclear that the antiatherogenic effects of antioxidants, if any, are due to inhibition of oxLDL formation. Thus, whether lowering oxLDL alone, rather than total LDL, affects ...