Time-dependent changes to lipids and antioxidants in plasma and aortas of apolipoprotein E knockout mice

Abstract

Oxidation of lipoproteins is thought to be an early event in atherogenesis. To evaluate whether aortic lipoprotein lipid (per)oxidation contributes to atherosclerosis, we investigated the time-dependent changes to lipids and antioxidants in plasma and aortas of apolipoprotein E gene knockout (apoE Ϫ / Ϫ ) mice receiving a high fat diet, and compared these changes with lesion development. Circulating buoyant lipoproteins and associated cholesterol (C), cholesteryl esters (CE), and ␣ -tocopherol ( ␣ -TOH) increased within 1 month then remained largely constant up to 6 months. Coenzyme Q (CoQ) remained unchanged for the first 3 months and increased marginally after 6 months. With increasing duration of the diet, plasma lipids showed an increased propensity to undergo peroxyl radical-induced (per)oxidation. Absolute concentrations of aortic C, hydroperoxides and hydroxides of CE (CE-O(O)H) and ␣ -TOH increased gradually while aortic CE increased more markedly with changes to cholesteryl linoleate being most pronounced. Aortic CoQ remained largely unchanged. Overall, the extent of aortic CE (per)oxidation remained low ( р 1%) and the ratio of incremental changes of ␣ -TOH to oxidizable lipid remained unchanged. Aortic biochemistry paralleled lesion formation, particularly that in the descending thoracic aorta. Together, our results show that progressing atherosclerosis in apoE Ϫ / Ϫ mice is associated with increased aortic lipid (per)oxidation as assessed by the concentrations of CE-O(O)H, measured directly by HPLC. This supports the oxidation theory. Measurement of aortic CE-O(O)H may be useful for mechanistic studies studying the relationship between inhibition of in vivo lipid (per)oxidation and atherosclerosis. -Letters, J.

Prevention of Atherosclerosis by Berries: The Case of Blueberries

“…The animal studies that provided direct evidence showing that blueberries could cause plaque in arteries to regress was published by Wu et al In this paper, the apolipoprotein-E-deficient (apoE –/– ) mouse model was used. This model has been widely used in cardiovascular research. , ApoE deficiency in mice leads to the development of atherosclerotic lesions, resembling those in humans . The mice were fed either the control diet or control diet supplemented with 1% freeze-dried wild blueberries for 20 weeks.…”

“…61,62 ApoE deficiency in mice leads to the development of atherosclerotic lesions, resembling those in humans. 63 The mice were fed either the control diet or control diet supplemented with 1% freeze-dried wild blueberries for 20 weeks. The plaques were measured at two sites on the aorta (arteries leading from the heart).…”

Destabilization of Atherosclerotic Plaque by Bilirubin Deficiency

“…Cholesteryl ester hydroperoxides are a major form of oxidized lipids in circulating lipoproteins, 15,16 while Prx2 is a highly abundant enzyme in red cells where it provides antioxidant protection against hydrogen peroxide and alkyl hydroperoxides by cycling between its reduced and disulfide oxidized forms, such that the redox state of Prx2 represents a sensitive in vivo maker of oxidative stress. 17 The increase in plasma cholesteryl ester hydroperoxides in Bvra −/− Apoe −/− TS mice was associated with a significant decrease in ubiquinol-9 (Table S1)—the major form of reduced coenzyme Q in mice 18 that forms the first line of antioxidant protection for lipoprotein-associated lipids. 16 Plasma concentrations of α-tocopherol were not significantly different between Bvra +/+ Apoe −/− and Bvra −/− Apoe −/− TS mice (Table S1).…”

“…All animal studies were approved by the Animal Welfare Committees of the Garvan Institute of Medical Research/St. Vincent's Hospital (protocol: [16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33], the University of New South Wales (protocol: 17-162B), and Sydney Local Health District (protocol: 2020-027). All procedures were performed according to the Guidelines for Animal Research outlined by the National Health and Medical Research Council of Australia and the Guide for the Care and Use of Laboratory Animals outlined by the National Institutes of Health.…”

Increased glycosphingolipid levels in serum and aortae of apolipoprotein E gene knockout mice

“…In addition to the morphological similarities of atherosclerotic lesions in the apoE Ϫ / Ϫ mouse and humans, several pathophysiological processes thought to contribute to atherosclerosis in humans also occur in the apoE Ϫ / Ϫ mouse. These include infiltration of CD4 ϩ T cells into the artery wall (7) and the partial oxidation of plasma lipoproteins and artery wall components (8)(9)(10). Inter-crossing of apoE Ϫ / Ϫ mice with P-selectin-deficient mice, immunodeficient (scid/scid) mice, or mice containing the osteopetrotic ( op ) mutation in the macrophage colony stimulating factor gene has been used to reveal the potential proatherogenic roles of P-selectin, CD4 ϩ T cells, and macrophages, respectively, in lesion development (11)(12)(13).…”