Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice.
BACKGROUND
The enzyme 12/15-lipoxygenase (12/15-LO) has been implicated in the oxidative modification of LDL. In a murine model, we tested the hypothesis that deletion of 12/15-LO decreases atherogenesis by reducing oxidant stress, as measured by 2 indices of lipid peroxidation: isoprostane generation and autoantibody formation to malondialdehyde (MDA)-LDL, an epitope of LDL formed as a result of oxidative modification.


RESULTS
12/15-LO-deficient (12/15-LO(-/-)) mice were crossed with apolipoprotein E-deficient (apoE(-/-)) mice. At 10 weeks of age, atherosclerotic lesion initiation was significantly delayed in the double-knockout mice. The rate of lesion progression was diminished at 8 and 12 months, and even at 15 months, lesion size was reduced 50% (P<0.0005) compared with control apoE(-/-) mice. The urinary and plasma levels of the specific isoprostane 8,12-iso-iPF(2alpha)-VI, as well as IgG autoantibodies against MDA-LDL, were significantly reduced in the double-deficient mice in parallel with decreased atherosclerosis at all time points from 10 weeks to 15 months of age compared with apoE(-/-) controls.


CONCLUSIONS
Enzymatic action of 12/15-LO contributes significantly to atherosclerotic lesion initiation and propagation in this murine model. Strong positive correlations exist between lesion size, isoprostane levels, and MDA-LDL autoantibodies, providing in vivo evidence for an enzymatic (12/15-LO) component to lipid peroxidation and atherogenesis.
Cyrus
T
T
Center for Experimental Therapeutics, Department of Medicine, University of Pennsylvania, Philadelphia, USA.
Praticò
D
D
Zhao
L
L
Witztum
J L
JL
Rader
D J
DJ
Rokach
J
J
FitzGerald
G A
GA
Funk
C D
CD
D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001092:Arachidonate 12-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics; D016718:Arachidonic Acid / Q000378:metabolism; D001161:Arteriosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001323:Autoantibodies / Q000097:blood; D002784:Cholesterol / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000097:blood / Q000652:urine; D004195:Disease Models, Animal; D018450:Disease Progression; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000502:physiology*; D008077:Lipoproteins, LDL / Q000276:immunology; D008315:Malondialdehyde / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
C115626:8,12-iso-isoprostane F2alpha-VI; D001057:Apolipoproteins E; D001323:Autoantibodies; D008076:Cholesterol, HDL; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D016718:Arachidonic Acid; D008315:Malondialdehyde; D002784:Cholesterol; D015237:Dinoprost; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase