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.
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.
Ng
Dominic S
DS
Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. ngd@smh.toronto.on.ca
Maguire
Graham F
GF
Wylie
John
J
Ravandi
Amir
A
Xuan
Wanli
W
Ahmed
Zakaria
Z
Eskandarian
Mohammad
M
Kuksis
Arnis
A
Connelly
Philip W
PW
D000483:Alleles; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D019540:Area Under Curve; D001161:Arteriosclerosis / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D043303:Aryldialkylphosphatase; D002853:Chromatography, Liquid; D004950:Esterases / Q000097:blood; D005838:Genotype; D028421:Isoprostanes / Q000097:blood; D007863:Lecithin Cholesterol Acyltransferase Deficiency / Q000235:genetics*; D008055:Lipids / Q000097:blood; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics* / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000737:chemistry*; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors
D001057:Apolipoproteins E; D028421:Isoprostanes; D008055:Lipids; D010713:Phosphatidylcholines; D013481:Superoxides; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D004950:Esterases; D043303:Aryldialkylphosphatase