Oxidative stress is markedly elevated in lecithin:cholesterol acyltransferase-deficient mice and is paradoxically reversed in the apolipoprotein E knockout background in association with a reduction in atherosclerosis
| Autor: | John Wylie, Dominic S. Ng, Amir Ravandi, Philip W. Connelly, Wanli Xuan, Graham F. Maguire, Zakaria Ahmed, Mohammad Eskandarian, Arnis Kuksis |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Apolipoprotein E
medicine.medical_specialty Time Factors Genotype Arteriosclerosis Sterol O-acyltransferase Isoprostanes medicine.disease_cause Biochemistry Phosphatidylcholine-Sterol O-Acyltransferase chemistry.chemical_compound Mice Apolipoproteins E Lecithin Cholesterol Acyltransferase Deficiency Superoxides Internal medicine medicine Animals Molecular Biology Hypoalphalipoproteinemia Alleles Aorta Mice Knockout biology Superoxide Aryldialkylphosphatase Paraoxonase Wild type Esterases Cell Biology medicine.disease Lipids Oxidative Stress Endocrinology chemistry Area Under Curve biology.protein Phosphatidylcholines Oxidative stress Lipoprotein Chromatography Liquid |
| Zdroj: | The Journal of biological chemistry. 277(14) |
| ISSN: | 0021-9258 |
| Popis: | Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare cause of severe hypoalphalipoproteinemia, but the affected subjects are surprisingly not particularly prone to premature coronary heart disease. We studied oxidative stress in lcat-/- mice and their cross-breed with apolipoprotein-E knockout mice (apoE-/-xlcat-/-) by measuring vascular ring superoxide production and plasma phospholipid (PL)-bound F2-isoprostane levels and their relationship with aortic atherosclerosis. Compared with wild type control (lcat+/+), lcat-/- and lcat+/- mice showed a 4.9- (p = 0.003) and a 2.1-fold (p = 0.04) increase in plasma PL-F2-isoprostane levels, respectively. There was also a 3.6- (p < 0.0001) and 2.9-fold (p = 0.003) increase in the area under the curve for the aortic ring superoxide excursion by lucigenin-derived chemiluminescence. A comparison of apoE-/-xlcat+/+ mice with wild type control mice showed a more modest 2.1- (p = 0.04) and 2.2-fold (p < 0.00001) increase in these respective markers. Surprisingly, the apoE-/-xlcat-/- mice showed a paradoxical normalization in both oxidation markers. Furthermore, by fast protein liquid chromatography separation, we observed an associated retention and redistribution of serum paraoxonase activities to the non-high density lipoprotein fractions in both the apoE-/-xlcat-/- and apoE-/-xlcat+/- mice. Aortic atherosclerotic lesions in male apoE-/-xlcat-/- and apoE-/-xlcat+/- mice were reduced by 52 (p = 0.02) and 24% (p = 0.46), respectively. Our data suggest that LCAT-deficient mice are associated with an increased oxidative stress that is paradoxically reversed in a hyperlipidemic background, possibly due to the redistribution of paraoxonase. This modulation of oxidative stress may in part contribute to the reduced atherosclerosis seen in the apoE-/- xlcat-/- mice. |
| Databáze: | OpenAIRE |
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