Impact of Plasma Oxidized Low-Density Lipoprotein Removal on Atherosclerosis

Abstract

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 ...

Age‐associated downregulation of vasohibin‐1 in vascular endothelial cells

“…Aortas were obtained and evaluated as Oil Red O‐stained areas, as described previously (Ishigaki et al ., 2008). Briefly, the aorta was dissected from surrounding tissues, cut open with the luminal surface facing up, and then immersion‐fixed in 10% neutral buffered formalin.…”

Dietary Cholesterol Oxidation Products Accelerate Plaque Destabilization and Rupture Associated with Monocyte Infiltration/Activation via the MCP-1-CCR2 Pathway in Mouse Brachiocephalic Arteries: Therapeutic Effects of Ezetimibe

“…To measure serum oxidized LDL levels, serum levels of lectin-like oxidized LDL receptor-1 (LOX-1) ligand were determined using a sandwich enzymelinked immunosorbent assay (ELISA), as described previously 28) . Serum LOX-1 ligand concentration was normalized to serum total cholesterol concentration (Cholesterol E-test; Wako Pure Chemical).…”

Serum lipid profile and hepatic evaluation in mice fed diet containing pequi nut or pulp (Caryocar brasiliense Camb.)

“…In particular, the oxidation of LDL is an important factor in this disease because it increases the expression of adhesion molecules that bind to circulating monocytes triggering the subsequent steps for the formation of lesions (CASÓS et al, 2008;ISHIGAKI et al, 2008;KATO et al, 2009). Therefore, the present study demonstrated that the diets containing pequi did not exert pro-atherogenic effect under these experimental conditions.…”